Dissecting CCL5 contribution to antigen specific T cell responses in head and neck cancers

Correlative studies of immune checkpoint blockade (ICB) show that response is highly dependent on the quantitative and qualitative status of pre-existing antitumor T cell clones. Of particular importance is the reservoir of tissue resident memory (TRM) T cells that positively correlate with response to ICB therapies. Our work in head and neck squamous cell carcinomas (HNSCCs) leads us to hypothesize that TRM T cells are major players in the early anti-tumor immune response to immunotherapy and that identifying specific chemokine and cytokine networks shaping the development and functionality of antitumor TRM cells will lead to improved therapeutic strategies. Using scRNASeq and scTCRseq of baseline and on treatment tumor samples from a novel neoadjuvant anti-PD1 HNSCC clinical trial (NCT02296684), we demonstrated that responding tumors had clonally expanded putative tumor specific exhausted CD8+ TILs with a TRM program, characterized by high cytotoxic potential and ZNF683 expression. By contrast, the non-responder baseline tumor microenvironment (TME) exhibited relative absence of cytotoxic ZNF683+ TILs and accumulation of highly exhausted clones. To define the determinants of TRM-development, we pursued mechanistic studies using anti-PD1 responsive or resistant HNSCC cell line syngeneic mouse models. This work confirmed that antitumor TRM-cell activity was positively correlated with increased frequency and functionality of type 1 conventional dendritic cells (cDC1) and with enhanced CCL5 chemokine expression in both human HNSCCs and mouse models. To expand our understanding of TME and tumor draining lymph node specific CCL5 dependent mechanisms underlying productive or ineffective T cell responses against HNSCC, we will dissect CCL5 driven remodeling of the TME including defining cellular sources and its target(s). We will extend these studies to human HNSCCs to dissect CCL5 and CCR5 contributions to DC:T cell interactions in fresh tumor explants. Finally, we will use a therapeutic approach with a novel oncolytic virus targeted to epidermal growth factor expressing tumor cells that anchors CCL5 in the TME. Together, this work will address the knowledge gap regarding the factors underlying cytotoxic versus dysfunctional antitumor tumor infiltrating lymphocytes in the HNSCC TME. Project Number: 1R01DE034386-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Ravindra Uppaluri (+1 co-PI) | Institution: DANA-FARBER CANCER INST, BOSTON, MA | Award Amount: $3,742,682 | Activity Code: R01 | Study Section: Translational Immuno-oncology Study Section[TIO] View on NIH RePORTER: https://reporter.nih.gov/project-details/11223832