Gomez-Roca, C. | Search bioRxiv

bioRxiv2026

Systemic neoantigen-specific T cells reveal central determinants of PD-(L)1 blockade efficacy

The contribution of neoantigen-specific T cells to PD-(L)1 efficacy has largely been inferred from tumor mutational burden. We functionally profiled circulating T cell responses against 7,038 predicted HLA-I-restricted and 21,453 HLA-II-restricted neopeptides in 27 patients with advanced non-small cell lung cancer treated with anti-PD-(L)1. CD4 responses were frequent and correlated with neoantigen availability but not clinical benefit. In contrast, the magnitude and breadth of neoantigen-specific CD8 T cell responses were associated with clinical benefit, progression-free and overall survival, independently of tumor mutational burden. Patients mounting coordinated CD4 and CD8 responses experienced improved progression-free survival. Tumors from CD8 responders displayed immune signatures indicative of both T cell priming and effector functions. Circulating neoantigen-specific CD8 T cells recognized endogenously processed antigens, trafficked to tumors, and selectively expanded under therapy while retaining CD28, CD226, and CXCR3 expression. These findings identify coordinated, functionally engaged neoantigen-specific T cell responses as central determinants of PD-(L)1 efficacy.

cancer biology↗

bioRxiv2021

Surveillance of in situ tumor arrays reveals early environmental control of cancer immunity

The immune phenotype of a tumor is a key predictor of its response to immunotherapy1-4. Patients who respond to immune checkpoint blockade generally present with tumors that are infiltrated by activated T cells, a tumor-immune phenotype referred to as immune inflamed5-7. However, not all immune inflamed tumors respond to therapy, and in addition the majority of patients presents with tumors that lack T cells ( immune desert) or that exclude T cells in the periphery of the tumor islet ( immune excluded)8. Despite the importance of these tumor-immune phenotypes in patients, little is known about their development, heterogeneity or dynamics due to an inability to model these features pre-clinically. Here, we describe an approach designated STAMP (skin tumor array by micro-poration), which combines in vivo noninvasive, high-throughput time-lapse imaging with excisional biopsies and next generation sequencing to characterize the establishment of the immunological niche and follow its evolution during immunotherapy. STAMP involves the seeding of dozens to hundreds clonal tumors in the superficial dermis of a single mouse ear that can be visualized in situ over weeks to months. Using this approach, we found that genetically identical tumors could display surprisingly different immune phenotypes. Although individual tumors of the same array were populated by the same T cell clonotypes, regression or progression of individual tumors were associated with distinct patterns of spatial organization of the T cells. In situ imaging of 14K tumors revealed that immune phenotypes were not static over-time but could rather evolve with tumor growth and response to treatment. Therapy-induced or spontaneous early conversion to the immune inflamed phenotype correlated with tumor regression and enhanced cytotoxic T cell activity. Therefore, STAMP provides a flexible approach to study the relationship between tumor evolution, immune cell dynamics, and tumor microenvironment with therapeutic response.

cancer biology↗