Impact of intratumor heterogeneity on anti-tumor immune responses in non-small cell lung cancer
Final Report Abstract
Cancer is a leading cause of death, with an urgent need for improved treatments. A form of cancer treatment that has seen unprecedented progress over the last decade is immunotherapy, which aims to make use of the immune system’s ability to detect and eradicate cancer cells. This ability is (among other) based on the recognition of Neoantigens (NeoAg) presented on the cancer cell surface. The presence of NeoAg and other targets that can be recognized by the immune system is a prerequisite for anti-tumor immune responses. Recent studies however have shown that not NeoAg abundance alone, but their clonality is of outstanding importance. While clonal NeoAg are expressed by all cells and drive potent immune responses, the expression of sub-clonal NeoAg is limited to a fraction of cells and is associated with poor immune responses. Abundance and clonality of NeoAg together constitute a NeoAg architecture, which recent reports indicate to be an important determinant for anti-tumor immune responses. It remained unknown however, how unfavorable NeoAg architectures impair anti-tumor immunity on a mechanistic level. To address this important gap in understanding, we developed a lung cancer mouse model with defined NeoAg architectures to decipher their impact on anti-tumor immunity. First, a reductionist model using pairs of NeoAg expressed in a tumor was used to uncover the rules of interplay between concurrent T cell responses. And next, complex NeoAg architectures were modelled to study the impact of this interplay in sub-clonal tumors and to identify tailored treatment strategies. We found that hierarchies are established between concurrent T cell responses to different NeoAg. In these hierarchies, T cell responses targeting the strongest (dominant) NeoAg are enhanced, whereas the outcome for non-dominant T cell responses can either be beneficial (NeoAg synergy) or detrimental (NeoAg competition). NeoAg synergy was observed for responses to low quality (weak) NeoAg and enhanced T cell expansion and infiltration into the tumor as well as the capability to kill target cells, leading to superior tumor control. Mechanistically, we found that T cell responses were enhanced due to a higher stimulatory capacity of dendritic cells, which are key orchestrators of T cell responses. Contrasting NeoAg synergy, T cell responses to high quality (strong), but sub-dominant NeoAg were suppressed. Here, a delay in T cell expansion, and a decrease in tumor infiltration were observed. This suppression was based on competition with the dominant NeoAg, leading to a reduction in dendritic cell-mediated T cell activation. When modelling sub-clonal tumors, we observed poor responses to immune-checkpoint blockade therapy (ICB), the currently most widely used form of immunotherapy. Resistance to ICB was enabled either by NeoAg architecture-induced suppression of sub-dominant T cell responses to strong NeoAg or insufficient induction of T cell responses against weak NeoAg. In both scenarios, unfavorable NeoAg architectures impaired the immune response and reduced tumor control. Strikingly, NeoAg-specific vaccines allowed to enhance suppressed immune responses and synergized with ICB to drastically improve control of sub-clonal tumors. Our study has important implications for the design of cancer vaccines and paves the way for the development of tailored treatment approaches for patients with sub-clonal tumors. Our data strongly suggests that combination treatment with cancer vaccines could let more cancer patients benefit from ICB.
Publications
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967 Unfavorable neoantigen architectures blunt anti-tumor T cell responses in a mouse model of lung adenocarcinoma. Regular and Young Investigator Award Abstracts, A1009-A1009. BMJ Publishing Group Ltd.
Roerden, Malte; Nguyen, Kim; Klop-Packel, Nory; Copeland, Christopher; Singh, Nishant; Birnbaum, Michael & Spranger, Stefani
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929 Mutual interactions between neoantigen-specific CD8+ T cell responses facilitate immune evasion in sub-clonal tumors. Regular and Young Investigator Award Abstracts, A1033-A1033. BMJ Publishing Group Ltd.
Roerden, Malte; Harake, Noora; Kim, Byungji; Cui, Yufei; White, Forest; Irvine, Darrell & Spranger, Stefani
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Decoupled neoantigen cross-presentation by dendritic cells limits anti-tumor immunity against tumors with heterogeneous neoantigen expression. eLife, 12.
Nguyen, Kim Bich; Roerden, Malte; Copeland, Christopher J.; Backlund, Coralie M.; Klop-Packel, Nory G.; Remba, Tanaka; Kim, Byungji; Singh, Nishant K.; Birnbaum, Michael E.; Irvine, Darrell J. & Spranger, Stefani
