Salvioni, A. | 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↗

bioRxiv2019

A virus hosted in malaria-infected blood protects against T cell-mediated inflammatory diseases by impairing DC function in a type I IFN-dependent manner

Co-infections shape the host immune status, thereby influencing the development of inflammatory diseases, which can result in detrimental or beneficial effects. For example, co-infections with concurrent Plasmodium species can alter malaria clinical evolution and malaria infection itself has the ability to modulate autoimmune reactions but, in both cases, the underlying mechanisms remain ill-defined.\n\nHere, we demonstrate that the protective effects of certain rodent malaria strains on T cell-mediated inflammatory pathologies are due to an RNA virus co-hosted in malaria-parasitized blood. We show that live as well as extracts of blood parasitized by P. berghei K173 or P. yoelii 17X YM, confer full protection against Pb ANKA (PbA)-induced Experimental Cerebral Malaria (ECM) and MOG/CFA-induced experimental autoimmune encephalomyelitis (EAE), and that this is associated with a strong type I IFN signature. We detected the presence of a viral element, the RNA virus Lactate Dehydrogenase-elevating Virus (LDV), in the protective Plasmodium stabilates and we established that infection with LDV alone recapitulates the protective effects on ECM and EAE. In ECM, we further show that protection results from an IFN-I-mediated reduction in the abundance of splenic conventional dendritic cell and in their ability to produce the Th1-inducing IL-12p70, leading to a decrease in pathogenic CD4+ Th1 responses. In EAE, protection is achieved by IFN-I mediated blunting of IL-12 and IL-23, preventing the differentiation of IFN-{gamma}-, IL-17- and GM-CSF-producing encephalitogenic CD4+ T cells.\n\nThus, our results identify a virus that is co-hosted in several Plasmodium stabilates across the community and has major consequences on the host immune system. Moreover, our data emphasize the importance of considering concurrent infections for the understanding of autoimmunity and malaria-associated inflammatory complications.

immunology↗