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1369 Engineering approaches to exploit MHC-II presentation on lung cancer cells | Journal for ImmunoTherapy of Cancer

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Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.. http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/." /> <meta name="DC.AccessRights" content="open-access" /> <meta name="DC.Description" content="Background Central to the success of immunotherapy is antigen presentation on Major Histocompatibility Class I and II (MHC-I and MHC-II).1 While much effort has been paid to characterize MHC-I antigens recognized by CD8+ T cells, our understanding of MHC-II antigens, which are recognized by CD4+ T cells, is far less developed. Notably, there is an increasing appreciation that CD4+ T cell recognition of MHC-II antigens plays a major role in immunotherapy responses, including tumor infiltrating lymphocyte (TIL) therapy and cancer vaccines.2–4 Most immunotherapy approaches rely on endogenous presentation of target antigens in the tumor microenvironment, which can be highly variable and is susceptible to immunoediting. Using results obtained from a novel preclinical model of lung adenocarcinoma (LUAD), we propose an alternative immunotherapy strategy that exploits direct MHC-II presentation on lung cancer cells to engineer antigen specific responses in the tumor microenvironment. Methods GEMMs, including the KrasLox-stop-Lox-G12D; p53fl/fl (KP), model faithfully recapitulate histopathological features of human LUAD and represent an excellent tool to understand MHC-II in the LUAD microenvironment.5 To profile MHC-II ligands in LUAD, we engineered a Cre-recombinase inducible affinity tagged MHC-II (H2-AbStrep) and incorporated this allele to the KP model (KP/AbStrep), enabling precise isolation of MHC-II peptides from malignant cells in the heterogeneous microenvironment. We thoroughly validated this novel model at the genetic, transcriptomic, and proteomic levels and isolated MHC-II peptides from LUAD tumors in different contexts and with different treatments. Results We demonstrate that LUAD cells present a diverse array of MHC-II peptides in vivo . Remarkably, we found that LUAD cells presented peptides that were derived from exogenous proteins, including those from the tumor microenvironment and systemic circulation. Leveraging this information, we engineered peptide conjugated-antibodies and peptide-loaded nanoparticles to hijack the presentation of exogenous material on LUAD cells. We found that multiple approaches can be utilized to introduce immunogenic MHC-II antigens to be presented directly by MHC-II on LUAD cells. Conclusions These results have profound implications for the implementation of next-generation immunotherapies. Instead of relying on the ability of cancer cells to endogenously present antigenic targets, our approach would enable designer antigens and complementary immunotherapies to be paired in a controlled and deliverable method. Beyond lung cancer, application of the AbStrep system to other disease and tissue contexts will pave the way forward for a deeper understanding of the MHC-II immunopeptidome in vivo to be exploited for next generation immunotherapies. References 1. 1 Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nature Reviews Cancer , 2021:1–15. https://doi.org:10.1038/s41568-021-00339-z. 2. Oliveira G, et al . Landscape of helper and regulatory antitumour CD4(+) T cells in melanoma. Nature 2022; 605 :532–538. https://doi.org:10.1038/s41586-022-04682-5. 3. Alspach E, et al . MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature 2019; 574 :696–701. https://doi.org:10.1038/s41586-019-1671-8. 4. Creelan BC, et al . Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nature Medicine 2021; 27 :1410–1418. https://doi.org:10.1038/s41591-021-01462-y. 5. Jaeger AM, et al . Deciphering the immunopeptidome in vivo reveals new tumour antigens. Nature 2022; 607 :149–155. https://doi.org:10.1038/s41586-022-04839-2." /> <meta name="DC.Contributor" content="Andrew Deonarine" /> <meta name="DC.Contributor" content="Andrew Weeden" /> <meta name="DC.Contributor" content="Emily Brennan" /> <meta name="DC.Contributor" content="Victoria Izumi" /> <meta name="DC.Contributor" content="William Rideout" /> <meta name="DC.Contributor" content="Tyler Jacks" /> <meta name="DC.Contributor" content="Bin Fang" /> <meta name="DC.Contributor" content="John Koomen" /> <meta name="DC.Contributor" content="Michael Dunne" /> <meta name="DC.Contributor" content="Paul Stewart" /> <meta name="DC.Contributor" content="Alex M Jaeger" /> <meta name="article:published_time" content="2024-11-01" /> <meta name="article:section" content="Regular and Young Investigator Award Abstracts" /> <meta name="citation_title" content="1369 Engineering approaches to exploit MHC-II presentation on lung cancer cells" /> <meta name="citation_abstract" lang="en" content="&lt;h3&gt;Background&lt;/h3&gt; &lt;p&gt;Central to the success of immunotherapy is antigen presentation on Major Histocompatibility Class I and II (MHC-I and MHC-II).&lt;sup&gt;1&lt;/sup&gt; While much effort has been paid to characterize MHC-I antigens recognized by CD8&lt;sup&gt;+&lt;/sup&gt; T cells, our understanding of MHC-II antigens, which are recognized by CD4&lt;sup&gt;+&lt;/sup&gt; T cells, is far less developed. Notably, there is an increasing appreciation that CD4&lt;sup&gt;+&lt;/sup&gt; T cell recognition of MHC-II antigens plays a major role in immunotherapy responses, including tumor infiltrating lymphocyte (TIL) therapy and cancer vaccines.&lt;sup&gt;2–4&lt;/sup&gt; Most immunotherapy approaches rely on endogenous presentation of target antigens in the tumor microenvironment, which can be highly variable and is susceptible to immunoediting. Using results obtained from a novel preclinical model of lung adenocarcinoma (LUAD), we propose an alternative immunotherapy strategy that exploits direct MHC-II presentation on lung cancer cells to engineer antigen specific responses in the tumor microenvironment.&lt;/p&gt;&lt;h3&gt;Methods&lt;/h3&gt; &lt;p&gt;GEMMs, including the Kras&lt;sup&gt;Lox-stop-Lox-G12D&lt;/sup&gt;; p53&lt;sup&gt;fl/fl&lt;/sup&gt; (KP), model faithfully recapitulate histopathological features of human LUAD and represent an excellent tool to understand MHC-II in the LUAD microenvironment.&lt;sup&gt;5&lt;/sup&gt; To profile MHC-II ligands in LUAD, we engineered a Cre-recombinase inducible affinity tagged MHC-II (H2-A&lt;sup&gt;b&lt;/sup&gt;Strep) and incorporated this allele to the KP model (KP/A&lt;sup&gt;b&lt;/sup&gt;Strep), enabling precise isolation of MHC-II peptides from malignant cells in the heterogeneous microenvironment. We thoroughly validated this novel model at the genetic, transcriptomic, and proteomic levels and isolated MHC-II peptides from LUAD tumors in different contexts and with different treatments.&lt;/p&gt;&lt;h3&gt;Results&lt;/h3&gt; &lt;p&gt;We demonstrate that LUAD cells present a diverse array of MHC-II peptides &lt;i&gt;in vivo&lt;/i&gt;. Remarkably, we found that LUAD cells presented peptides that were derived from exogenous proteins, including those from the tumor microenvironment and systemic circulation. Leveraging this information, we engineered peptide conjugated-antibodies and peptide-loaded nanoparticles to hijack the presentation of exogenous material on LUAD cells. We found that multiple approaches can be utilized to introduce immunogenic MHC-II antigens to be presented directly by MHC-II on LUAD cells.&lt;/p&gt;&lt;h3&gt;Conclusions&lt;/h3&gt; &lt;p&gt;These results have profound implications for the implementation of next-generation immunotherapies. Instead of relying on the ability of cancer cells to endogenously present antigenic targets, our approach would enable designer antigens and complementary immunotherapies to be paired in a controlled and deliverable method. Beyond lung cancer, application of the A&lt;sup&gt;b&lt;/sup&gt;Strep system to other disease and tissue contexts will pave the way forward for a deeper understanding of the MHC-II immunopeptidome &lt;i&gt;in vivo&lt;/i&gt; to be exploited for next generation immunotherapies.&lt;/p&gt;&lt;h3&gt;References&lt;/h3&gt; &lt;p&gt;1 Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. &lt;i&gt;Nature Reviews Cancer&lt;/i&gt;, 2021:1–15. https://doi.org:10.1038/s41568-021-00339-z.&lt;/p&gt;&lt;p&gt;Oliveira G,&lt;i&gt; et al&lt;/i&gt;. Landscape of helper and regulatory antitumour CD4(+) T cells in melanoma. &lt;i&gt;Nature&lt;/i&gt; 2022;&lt;b&gt;605&lt;/b&gt;:532–538. https://doi.org:10.1038/s41586-022-04682-5.&lt;/p&gt;&lt;p&gt;Alspach E,&lt;i&gt; et al&lt;/i&gt;. MHC-II neoantigens shape tumour immunity and response to immunotherapy. &lt;i&gt;Nature&lt;/i&gt; 2019;&lt;b&gt;574&lt;/b&gt;:696–701. https://doi.org:10.1038/s41586-019-1671-8.&lt;/p&gt;&lt;p&gt;Creelan BC,&lt;i&gt; et al&lt;/i&gt;. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. &lt;i&gt;Nature Medicine&lt;/i&gt; 2021;&lt;b&gt;27&lt;/b&gt;:1410–1418. https://doi.org:10.1038/s41591-021-01462-y.&lt;/p&gt;&lt;p&gt;Jaeger AM,&lt;i&gt; et al&lt;/i&gt;. Deciphering the immunopeptidome in vivo reveals new tumour antigens. &lt;i&gt;Nature&lt;/i&gt; 2022;&lt;b&gt;607&lt;/b&gt;:149–155. https://doi.org:10.1038/s41586-022-04839-2.&lt;/p&gt;" /> <meta name="citation_journal_title" content="Journal for ImmunoTherapy of Cancer" /> <meta name="citation_publisher" content="BMJ Specialist Journals" /> <meta name="citation_publication_date" content="2024/11/01" /> <meta name="citation_mjid" content="jitc;12/Suppl_2/A1533" /> <meta name="citation_id" content="12/Suppl_2/A1533" /> <meta name="citation_public_url" content="https://jitc.bmj.com/content/12/Suppl_2/A1533" /> <meta name="citation_abstract_html_url" content="https://jitc.bmj.com/content/12/Suppl_2/A1533.abstract" /> <meta name="citation_full_html_url" content="https://jitc.bmj.com/content/12/Suppl_2/A1533.full" /> <meta name="citation_pdf_url" content="https://jitc.bmj.com/content/jitc/12/Suppl_2/A1533.full.pdf" /> <meta name="citation_issn" content="2051-1426" /> <meta name="citation_journal_abbrev" content="J Immunother Cancer" /> <meta name="citation_doi" content="10.1136/jitc-2024-SITC2024.1369" /> <meta name="citation_volume" content="12" /> <meta name="citation_issue" content="Suppl 2" /> <meta name="citation_article_type" content="Meeting Report" /> <meta name="citation_section" content="Regular and Young Investigator Award Abstracts" /> <meta name="citation_access" content="all" /> <meta name="citation_author" content="Andrew Deonarine" /> <meta name="citation_author_institution" content="H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA" /> <meta name="citation_author" content="Andrew Weeden" /> <meta name="citation_author_institution" content="H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA" /> <meta name="citation_author" content="Emily Brennan" /> <meta name="citation_author_institution" content="H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA" /> <meta name="citation_author" content="Victoria Izumi" /> <meta name="citation_author_institution" content="H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA" /> <meta name="citation_author" content="William Rideout" /> <meta name="citation_author_institution" content="Koch Institute at MIT, Cambridge, MA, USA" /> <meta name="citation_author" content="Tyler Jacks" /> <meta name="citation_author_institution" content="Koch Institute at MIT, Cambridge, MA, USA" /> <meta name="citation_author" content="Bin Fang" /> <meta name="citation_author_institution" content="H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA" /> <meta name="citation_author" content="John Koomen" /> <meta name="citation_author_institution" content="H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA" /> <meta name="citation_author" content="Michael Dunne" /> <meta name="citation_author_institution" content="H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA" /> <meta name="citation_author" content="Paul Stewart" /> <meta name="citation_author_institution" content="H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA" /> <meta name="citation_author" content="Alex M Jaeger" /> <meta name="citation_author_institution" content="H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA" /> <meta name="citation_fulltext_world_readable" content="" /> <meta name="twitter:title" content="1369 Engineering approaches to exploit MHC-II presentation on lung cancer cells" /> <meta name="twitter:card" content="summary" /> <meta name="twitter:description" content="Background Central to the success of immunotherapy is antigen presentation on Major Histocompatibility Class I and II (MHC-I and MHC-II).1 While much effort has been paid to characterize MHC-I antigens recognized by CD8+ T cells, our understanding of MHC-II antigens, which are recognized by CD4+ T cells, is far less developed. Notably, there is an increasing appreciation that CD4+ T cell recognition of MHC-II antigens plays a major role in immunotherapy responses, including tumor infiltrating lymphocyte (TIL) therapy and cancer vaccines.2–4 Most immunotherapy approaches rely on endogenous presentation of target antigens in the tumor microenvironment, which can be highly variable and is susceptible to immunoediting. Using results obtained from a novel preclinical model of lung adenocarcinoma (LUAD), we propose an alternative immunotherapy strategy that exploits direct MHC-II presentation on lung cancer cells to engineer antigen specific responses in the tumor microenvironment. Methods GEMMs, including the KrasLox-stop-Lox-G12D; p53fl/fl (KP), model faithfully recapitulate histopathological features of human LUAD and represent an excellent tool to understand MHC-II in the LUAD microenvironment.5 To profile MHC-II ligands in LUAD, we engineered a Cre-recombinase inducible affinity tagged MHC-II (H2-AbStrep) and incorporated this allele to the KP model (KP/AbStrep), enabling precise isolation of MHC-II peptides from malignant cells in the heterogeneous microenvironment. We thoroughly validated this novel model at the genetic, transcriptomic, and proteomic levels and isolated MHC-II peptides from LUAD tumors in different contexts and with different treatments. Results We demonstrate that LUAD cells present a diverse array of MHC-II peptides in vivo . Remarkably, we found that LUAD cells presented peptides that were derived from exogenous proteins, including those from the tumor microenvironment and systemic circulation. Leveraging this information, we engineered peptide conjugated-antibodies and peptide-loaded nanoparticles to hijack the presentation of exogenous material on LUAD cells. We found that multiple approaches can be utilized to introduce immunogenic MHC-II antigens to be presented directly by MHC-II on LUAD cells. Conclusions These results have profound implications for the implementation of next-generation immunotherapies. Instead of relying on the ability of cancer cells to endogenously present antigenic targets, our approach would enable designer antigens and complementary immunotherapies to be paired in a controlled and deliverable method. Beyond lung cancer, application of the AbStrep system to other disease and tissue contexts will pave the way forward for a deeper understanding of the MHC-II immunopeptidome in vivo to be exploited for next generation immunotherapies. References 1. 1 Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nature Reviews Cancer , 2021:1–15. https://doi.org:10.1038/s41568-021-00339-z. 2. Oliveira G, et al . Landscape of helper and regulatory antitumour CD4(+) T cells in melanoma. Nature 2022; 605 :532–538. https://doi.org:10.1038/s41586-022-04682-5. 3. Alspach E, et al . MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature 2019; 574 :696–701. https://doi.org:10.1038/s41586-019-1671-8. 4. Creelan BC, et al . Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nature Medicine 2021; 27 :1410–1418. https://doi.org:10.1038/s41591-021-01462-y. 5. Jaeger AM, et al . Deciphering the immunopeptidome in vivo reveals new tumour antigens. Nature 2022; 607 :149–155. https://doi.org:10.1038/s41586-022-04839-2." /> <meta name="og-title" property="og:title" content="1369 Engineering approaches to exploit MHC-II presentation on lung cancer cells" /> <meta name="og-url" property="og:url" content="https://jitc.bmj.com/content/12/Suppl_2/A1533" /> <meta name="og-site-name" property="og:site_name" content="Journal for ImmunoTherapy of Cancer" /> <meta name="og-description" property="og:description" content="Background Central to the success of immunotherapy is antigen presentation on Major Histocompatibility Class I and II (MHC-I and MHC-II).1 While much effort has been paid to characterize MHC-I antigens recognized by CD8+ T cells, our understanding of MHC-II antigens, which are recognized by CD4+ T cells, is far less developed. Notably, there is an increasing appreciation that CD4+ T cell recognition of MHC-II antigens plays a major role in immunotherapy responses, including tumor infiltrating lymphocyte (TIL) therapy and cancer vaccines.2–4 Most immunotherapy approaches rely on endogenous presentation of target antigens in the tumor microenvironment, which can be highly variable and is susceptible to immunoediting. Using results obtained from a novel preclinical model of lung adenocarcinoma (LUAD), we propose an alternative immunotherapy strategy that exploits direct MHC-II presentation on lung cancer cells to engineer antigen specific responses in the tumor microenvironment. Methods GEMMs, including the KrasLox-stop-Lox-G12D; p53fl/fl (KP), model faithfully recapitulate histopathological features of human LUAD and represent an excellent tool to understand MHC-II in the LUAD microenvironment.5 To profile MHC-II ligands in LUAD, we engineered a Cre-recombinase inducible affinity tagged MHC-II (H2-AbStrep) and incorporated this allele to the KP model (KP/AbStrep), enabling precise isolation of MHC-II peptides from malignant cells in the heterogeneous microenvironment. We thoroughly validated this novel model at the genetic, transcriptomic, and proteomic levels and isolated MHC-II peptides from LUAD tumors in different contexts and with different treatments. Results We demonstrate that LUAD cells present a diverse array of MHC-II peptides in vivo . Remarkably, we found that LUAD cells presented peptides that were derived from exogenous proteins, including those from the tumor microenvironment and systemic circulation. Leveraging this information, we engineered peptide conjugated-antibodies and peptide-loaded nanoparticles to hijack the presentation of exogenous material on LUAD cells. We found that multiple approaches can be utilized to introduce immunogenic MHC-II antigens to be presented directly by MHC-II on LUAD cells. Conclusions These results have profound implications for the implementation of next-generation immunotherapies. Instead of relying on the ability of cancer cells to endogenously present antigenic targets, our approach would enable designer antigens and complementary immunotherapies to be paired in a controlled and deliverable method. Beyond lung cancer, application of the AbStrep system to other disease and tissue contexts will pave the way forward for a deeper understanding of the MHC-II immunopeptidome in vivo to be exploited for next generation immunotherapies. References 1. 1 Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. Nature Reviews Cancer , 2021:1–15. https://doi.org:10.1038/s41568-021-00339-z. 2. Oliveira G, et al . Landscape of helper and regulatory antitumour CD4(+) T cells in melanoma. Nature 2022; 605 :532–538. https://doi.org:10.1038/s41586-022-04682-5. 3. Alspach E, et al . MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature 2019; 574 :696–701. https://doi.org:10.1038/s41586-019-1671-8. 4. Creelan BC, et al . Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. Nature Medicine 2021; 27 :1410–1418. https://doi.org:10.1038/s41591-021-01462-y. 5. Jaeger AM, et al . Deciphering the immunopeptidome in vivo reveals new tumour antigens. 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pane-highwire-article-citation col-mobile-10 col-narrow-10 col-normal-11 article-title" > <div class="pane-content"> <div class="highwire-article-citation highwire-citation-type-highwire-article node56311" data-node-nid="56311" id="node-56311--2154591862" data-pisa="jitc;12/Suppl_2/A1533" data-pisa-master="jitc;jitc-2024-SITC2024.1369" data-apath="/jitc/12/Suppl_2/A1533.atom"><cite class="highwire-cite highwire-cite-highwire-article highwire-citation-bmjj-title clearfix"> <div class="highwire-cite-title">1369 Engineering approaches to exploit MHC-II presentation on lung cancer cells</div> <span class="highwire-cite-access"><span class="highwire-citation-access"><svg class="icon icon-open-access bmjj-open-access bmjj-access-tag"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-openaccess"></use><svg></svg></svg></span></span> </cite> </div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-panel-tabs-container col-narrow-12 clear" > <div class="pane-content"> <div data-panels-ajax-tab-preloaded="jnl_template_bmjj_tab_art" id="panels-ajax-tab-container-highwire_article_tabs" class="panels-ajax-tab-container"><div class="panels-ajax-tab-loading" style ="display:none"><img class="loading" src="https://jitc.bmj.com/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif" alt="Loading" title="Loading" /></div><div class="panels-ajax-tab-wrap-jnl_template_bmjj_tab_art"><div class="panel-display panel-1col clearfix" > <div class="panel-panel panel-col"> <div><div class="panel-pane pane-highwire-markup author-affiliates col-narrow-12 author-affiliates-corresp article" > <div class="pane-content"> <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div xmlns:xhtml="http://www.w3.org/1999/xhtml" class="contributors"><ol class="contributor-list" id="contrib-group-1"><li class="contributor" id="contrib-1"><span class="name">Andrew Deonarine</span><a id="xref-aff-1-1" class="xref-aff" href="#aff-1">1</a>, </li><li class="contributor" id="contrib-2"><span class="name">Andrew Weeden</span><a id="xref-aff-1-2" class="xref-aff" href="#aff-1">1</a>, </li><li class="contributor" id="contrib-3"><span class="name">Emily Brennan</span><a id="xref-aff-1-3" class="xref-aff" href="#aff-1">1</a>, </li><li class="contributor" id="contrib-4"><span class="name">Victoria Izumi</span><a id="xref-aff-1-4" class="xref-aff" href="#aff-1">1</a>, </li><li class="contributor" id="contrib-5"><span class="name">William Rideout</span><a id="xref-aff-2-1" class="xref-aff" href="#aff-2">2</a>, </li><li class="contributor" id="contrib-6"><span class="name">Tyler Jacks</span><a id="xref-aff-2-2" class="xref-aff" href="#aff-2">2</a>, </li><li class="contributor" id="contrib-7"><span class="name">Bin Fang</span><a id="xref-aff-1-5" class="xref-aff" href="#aff-1">1</a>, </li><li class="contributor" id="contrib-8"><span class="name">John Koomen</span><a id="xref-aff-1-6" class="xref-aff" href="#aff-1">1</a>, </li><li class="contributor" id="contrib-9"><span class="name">Michael Dunne</span><a id="xref-aff-1-7" class="xref-aff" href="#aff-1">1</a>, </li><li class="contributor" id="contrib-10"><span class="name">Paul Stewart</span><a id="xref-aff-1-8" class="xref-aff" href="#aff-1">1</a> and </li><li class="last" id="contrib-11"><span class="name">Alex M Jaeger</span><a id="xref-aff-1-9" class="xref-aff" href="#aff-1">1</a></li></ol><ol class="affiliation-list"><li class="aff"><a id="aff-1" name="aff-1"></a><address> <sup>1</sup>H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA</address></li><li class="aff"><a id="aff-2" name="aff-2"></a><address> <sup>2</sup>Koch Institute at MIT, Cambridge, MA, USA</address></li></ol><ul class="author-notes"><li class="fn" id="fn-1"><p id="p-1">Journal for ImmunoTherapy of Cancer (JITC) preprint. The copyright holder for this preprint are the authors/funders, who have granted JITC permission to display the preprint. All rights reserved. No reuse allowed without permission.</p></li></ul></div></div></div> </div> </div> <div class="panel-separator"></div><div class="panel-pane pane-highwire-markup abstract-with-bc" > <div class="pane-content"> <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" id="content-block" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="article abstract-view "><span class="highwire-journal-article-marker-start"></span><div class="section abstract" id="abstract-1"><h2>Abstract</h2><div id="sec-1" class="subsection"><p id="p-3"><strong>Background</strong> Central to the success of immunotherapy is antigen presentation on Major Histocompatibility Class I and II (MHC-I and MHC-II).<sup>1</sup> While much effort has been paid to characterize MHC-I antigens recognized by CD8<sup>+</sup> T cells, our understanding of MHC-II antigens, which are recognized by CD4<sup>+</sup> T cells, is far less developed. Notably, there is an increasing appreciation that CD4<sup>+</sup> T cell recognition of MHC-II antigens plays a major role in immunotherapy responses, including tumor infiltrating lymphocyte (TIL) therapy and cancer vaccines.<sup>2–4</sup> Most immunotherapy approaches rely on endogenous presentation of target antigens in the tumor microenvironment, which can be highly variable and is susceptible to immunoediting. Using results obtained from a novel preclinical model of lung adenocarcinoma (LUAD), we propose an alternative immunotherapy strategy that exploits direct MHC-II presentation on lung cancer cells to engineer antigen specific responses in the tumor microenvironment.</p></div><div id="sec-2" class="subsection"><p id="p-4"><strong>Methods</strong> GEMMs, including the Kras<sup>Lox-stop-Lox-G12D</sup>; p53<sup>fl/fl</sup> (KP), model faithfully recapitulate histopathological features of human LUAD and represent an excellent tool to understand MHC-II in the LUAD microenvironment.<sup>5</sup> To profile MHC-II ligands in LUAD, we engineered a Cre-recombinase inducible affinity tagged MHC-II (H2-A<sup>b</sup>Strep) and incorporated this allele to the KP model (KP/A<sup>b</sup>Strep), enabling precise isolation of MHC-II peptides from malignant cells in the heterogeneous microenvironment. We thoroughly validated this novel model at the genetic, transcriptomic, and proteomic levels and isolated MHC-II peptides from LUAD tumors in different contexts and with different treatments.</p></div><div id="sec-3" class="subsection"><p id="p-5"><strong>Results</strong> We demonstrate that LUAD cells present a diverse array of MHC-II peptides <em>in vivo</em>. Remarkably, we found that LUAD cells presented peptides that were derived from exogenous proteins, including those from the tumor microenvironment and systemic circulation. Leveraging this information, we engineered peptide conjugated-antibodies and peptide-loaded nanoparticles to hijack the presentation of exogenous material on LUAD cells. We found that multiple approaches can be utilized to introduce immunogenic MHC-II antigens to be presented directly by MHC-II on LUAD cells.</p></div><div id="sec-4" class="subsection"><p id="p-6"><strong>Conclusions</strong> These results have profound implications for the implementation of next-generation immunotherapies. Instead of relying on the ability of cancer cells to endogenously present antigenic targets, our approach would enable designer antigens and complementary immunotherapies to be paired in a controlled and deliverable method. Beyond lung cancer, application of the A<sup>b</sup>Strep system to other disease and tissue contexts will pave the way forward for a deeper understanding of the MHC-II immunopeptidome <em>in vivo</em> to be exploited for next generation immunotherapies.</p></div><div id="sec-5" class="subsection"><p><strong>References</strong></p><ol class="list-ord " id="list-1"><li id="list-item-1"><p id="p-7">1 Jhunjhunwala S, Hammer C, Delamarre L. Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion. <em>Nature Reviews Cancer</em>, 2021:1–15. https://doi.org:10.1038/s41568-021-00339-z.</p></li><li id="list-item-2"><p id="p-8">Oliveira G,<em> et al</em>. Landscape of helper and regulatory antitumour CD4(+) T cells in melanoma. <em>Nature</em> 2022;<strong>605</strong>:532–538. https://doi.org:10.1038/s41586-022-04682-5.</p></li><li id="list-item-3"><p id="p-9">Alspach E,<em> et al</em>. MHC-II neoantigens shape tumour immunity and response to immunotherapy. <em>Nature</em> 2019;<strong>574</strong>:696–701. https://doi.org:10.1038/s41586-019-1671-8.</p></li><li id="list-item-4"><p id="p-10">Creelan BC,<em> et al</em>. Tumor-infiltrating lymphocyte treatment for anti-PD-1-resistant metastatic lung cancer: a phase 1 trial. <em>Nature Medicine</em> 2021;<strong>27</strong>:1410–1418. https://doi.org:10.1038/s41591-021-01462-y.</p></li><li id="list-item-5"><p id="p-11">Jaeger AM,<em> et al</em>. Deciphering the immunopeptidome in vivo reveals new tumour antigens. <em>Nature</em> 2022;<strong>607</strong>:149–155. https://doi.org:10.1038/s41586-022-04839-2.</p></li></ol></div></div><div class="license" id="license-1"><span class="ali-license-ref"><a href="http://creativecommons.org/licenses/by-nc/4.0/" rel="license">http://creativecommons.org/licenses/by-nc/4.0/</a></span><p id="p-2">This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. 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