Impaired T cell and neoantigen retention in time serial analysis of metastatic non-small cell lung cancer in patients unresponsive to TIL cell therapy
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PROVIDER: PRJNA1233314 | ENA |
REPOSITORIES: ENA
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Project description:Cell therapy with tumor-infiltrating lymphocytes (TIL) has yielded durable responses for multiple cancer types, but the causes of therapeutic resistance remain largely unknown. Here multi-dimensional analysis was performed on time serial tumor and blood in a lung cancer TIL therapy trial. Using T-cell receptor sequencing on both functionally expanded T cells and neoantigen-loaded tetramer-sorted T cells, we identified neoantigen specific TCRs. We then mapped clones into individual transcriptomes and found that neoantigen-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit. Tracking neoantigen-reactive clonotypes over time, decay of antigen-reactive peripheral T-cell clonotypes was associated with the emergence of progressive disease. Further, subclonal neoantigens previously targeted by infused T cells were subsequently absent within tumors at progression, suggesting potential adaptive resistance. Our findings suggest that targeting clonal antigens and circumventing dysfunctional states may be important for conferring clinical responses to TIL therapy.
2024-12-30 | PXD049438 | Pride
Project description:Cell therapy with tumor-infiltrating lymphocytes (TIL) has yielded durable responses for multiple cancer types, but the causes of therapeutic resistance remain largely unknown. Here multi-dimensional analysis was performed on time serial tumor and blood in a lung cancer TIL therapy trial. Using T-cell receptor sequencing on both functionally expanded T cells and neoantigen-loaded tetramer-sorted T cells, we identified tumor antigen specific TCRs. We then mapped clones into individual transcriptomes and found that tumor-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit. Tracking tumor-reactive clonotypes over time, decay of antigen-reactive peripheral T-cell clonotypes was associated with the emergence of progressive disease. Further, subclonal neoantigens previously targeted by infused T cells were subsequently absent within tumors at progression, suggesting potential adaptive resistance. Our findings suggest that targeting clonal antigens and circumventing dysfunctional states may be important for conferring clinical responses to TIL therapy.
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Project description:We mapped TIL clones into individual transcriptomes and found that neoantigen-reactive clonotypes expressed a dysfunctional program and lacked stem-like features among patients who lacked clinical benefit.
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Project description:Impaired T cell and neoantigen retention in time serial analysis of lung cancer patients treated with TIL cell therapy
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Project description:Neoantigen-reactive cytotoxic T lymphocytes play a vital role in precise cancer cell elimination. In this study, we demonstrate the effectiveness of personalized neoantigen-based T cell therapy in inducing tumor regression in two patients suffering from heavily-burdened metastatic ovarian cancer. Our approach involved the development of a robust pipeline for ex vivo expansion of neoantigen-reactive T lymphocytes. Neoantigen peptides were designed and synthesized based on the somatic mutations of the tumors and their predicted HLA binding affinities. These peptides were then presented to T lymphocytes through co-culture with neoantigen-loaded dendritic cells for ex vivo expansion. Subsequent to cell therapy, both patients exhibited significant reductions in tumor marker levels and experienced substantial tumor regression. One patient achieved repeated cancer regression through infusions of T cell products generated from newly identified neoantigens. Transcriptomic analyses revealed a remarkable increase in neoantigen-reactive cytotoxic lymphocytes in the peripheral blood of the patients following cell therapy. These cytotoxic T lymphocytes expressed polyclonal T cell receptors (TCR) against neoantigens, along with abundant cytotoxic proteins and pro-inflammatory cytokines. The efficacy of neoantigen targeting was significantly associated with the immunogenicity and TCR polyclonality. Notably, the neoantigen-specific TCR clonotypes persisted in the peripheral blood after cell therapy. Our findings indicate that personalized neoantigen-based T cell therapy triggers cytotoxic lymphocytes expressing polyclonal TCR against ovarian cancer, suggesting its promising potential in cancer immunotherapy.
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Project description:Neoantigen-specific T cells specifically recognize tumor cells and are critical for cancer immunotherapies. However, the transcriptional program controlling the cell fate decisions by neoantigen-specific T cells is incompletely understood. Here, using joint single-cell transcriptome and TCR profiling, we mapped the clonal expansion and differentiation of neoantigen-specific CD8+ T cells in the tumor and draining lymph node in mouse prostate cancer. Compared to other antitumor CD8+ T cells and bystanders, neoantigen-specific CD8+ tumor-infiltrating T cells (TILs) upregulated gene signatures of T cell activation and exhaustion. In the tumor draining lymph node, we identified TCF1+TOX- TSCM, TCF1+TOX+ TPEX, and TCF1-TOX+ effector-like TEX subsets among neoantigen-specific CD8+ T cells. Clonal tracing analysis of neoantigen-specific CD8+ T cells revealed greater clonal expansion in divergent clones and less expansion in clones biased towards TEX, TPEX, or TSCM. The TPEX subset had greater clonal diversity and likely represented the root of neoantigen-specific CD8+ T cell differentiation, whereas highly clonally expanded effector-like TEX cells were positioned at the branch point where neoantigen-specific clones exited the lymph node and differentiated into TEX TILs. Notably, TSCM differentiation of neoantigen-specific CD8+ clones in the lymph node negatively correlated with exhaustion and clonal expansion of the same clones in the tumor. In addition, the gene signature of neoantigen-specific clones biased toward tumor infiltration relative to lymph node residence predicted a poorer response to immune checkpoint inhibitor. Together, we identified the transcriptional program that controls the cell fate choices by neoantigen-specific CD8+ T cells and correlates with clinical outcomes in cancer patients.
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Project description:Neoantigens are promising immunogens for cancer vaccines and are traditionally delivered as adjuvanted peptide vaccines. Our goal was to understand how an adenoviral vectored neoantigen vaccine would induce tumor immunity compared to a peptide neoantigen vaccine. We generated adenovirus serotype 26 (Ad26) vaccines encoding MC38-specific neoantigens and compared them to an adjuvanted peptide MC38 neoantigen vaccine. The single-shot Ad26 vaccines induced greater neoantigen specific IFN- CD8+ T cell immune responses than the two-shot adjuvanted peptide vaccine in mice, and Ad26.VP22.7Epi also provided superior protective efficacy compared to the peptide vaccine following tumor challenge. Ad26.VP22.7Epi induced a robust immunodominant CD8+ T cell response against the Adpgk neoantigen, while the peptide vaccine induced lower responses against both Adpgk and Reps1 neoantigens. Tumor infiltrating lymphocytes (TILs) from both vaccine groups were analyzed using scRNA-seq and TCR-seq. Vaccinated mice showed increased CD8+ T cell infiltration, with the peptide vaccine inducing more infiltrating CD8+ T cells than the Ad26.VP22.7Epi vaccine. However, Ad26.VP22.7Epi induced CD8+ T cells showed more upregulation of T cell maturation, activation, and Th1 pathways compared to peptide vaccine induced CD8+ T cells, suggesting improved functional T cell quality. TCR-seq of these TILs also demonstrated that Ad26.VP22.7Epi generated larger T cell hyperexpanded clones compared to the peptide vaccine. These results suggest that the Ad26.VP22.7Epi vaccine led to improved tumor control compared with the peptide vaccine due to increased T cell hyperexpansion and functional activation. Our data suggest that future cancer vaccine development strategies should focus on inducing functional hyperexpanded CD8+ T cell responses and not only maximizing tumor infiltrating CD8+ T cell numbers.
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Project description:Adoptive cell transfer (ACT) using neoantigen-specific T cells is an effective immunotherapeutic strategy. However, the difficulty in identifying and screening neoantigen-specific T cells limits its widespread application. Here, we prepared neoantigen-reactive T cells (NRTs) after immunization with a tumor lysate-loaded dendritic cell (DC) vaccine (OCDC) for ACT. Our results demonstrated that the OCDC vaccine could induce a neoantigen-specific immune response, and it was feasible to prepare NRTs by loading immunogenic neoantigens onto DCs and coculturing them with spleen lymphocytes from mice immunized with the OCDC vaccine. We then transferred these NRTs back to the LL/2 tumor-bearing mice after OCDC vaccine immunization and found that OCDC vaccine and NRTs adoptive transfer combination treatment could induce a stronger antitumor response. Furthermore, we found that infused NRTs could migrate into the tumor microenvironment to exert antitumor effects. Our research provides a new and convenient method of preparing NRTs for ACT. The clinical translation of this approach has the potential to increase ACT efficacy.
2024-07-05 | GSE271086 | GEO
Project description:Adoptive cell transfer (ACT) using neoantigen-specific T cells is an effective immunotherapeutic strategy. However, the difficulty in identifying and screening neoantigen-specific T cells limits its widespread application. Here, we prepared neoantigen-reactive T cells (NRTs) after immunization with a tumor lysate-loaded dendritic cell (DC) vaccine (OCDC) for ACT. Our results demonstrated that the OCDC vaccine could induce a neoantigen-specific immune response, and it was feasible to prepare NRTs by loading immunogenic neoantigens onto DCs and coculturing them with spleen lymphocytes from mice immunized with the OCDC vaccine. We then transferred these NRTs back to the LL/2 tumor-bearing mice after OCDC vaccine immunization and found that OCDC vaccine and NRTs adoptive transfer combination treatment could induce a stronger antitumor response. Furthermore, we found that infused NRTs could migrate into the tumor microenvironment to exert antitumor effects. Our research provides a new and convenient method of preparing NRTs for ACT. The clinical translation of this approach has the potential to increase ACT efficacy.
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