Tissue-resident Memory and Circulating T cells are Early Responders to Pre-surgical Cancer Immunotherapy
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PROVIDER: PRJNA827834 | ENA |
REPOSITORIES: ENA
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Project description:Abstract: Purpose: We evaluated whether IDO-inhibitor BMS986205 (IDOi) + PD-1 inhibitor nivolumab enhanced T-cell activity and augmented immune-mediated antitumor responses in untreated, resectable HNSCC. We employed response-adaptive surgical timing to identify responders to immunotherapy and enhance their response. Patients and Methods: Patients with HNSCC were 3:1 randomized to receive nivolumab with or without BMS986205 PO daily (NCT03854032). In the combination arm, BMS986205 was initiated 7 days prior to nivolumab. Patients were stratified by HPV status. Response-adaptive surgical timing involved response assessment by radiographic criteria 4 weeks after nivolumab in both arms. Non-responders underwent surgical resection, while responders received 4 more weeks of randomized therapy before surgery. Biomarker analysis utilized pathologic treatment response (pTR) and RNA sequencing. Results: Forty-two patients were enrolled, and the addition of IDOi to nivolumab did not result in greater rate of radiographic response (p=0.909). Treatment was well-tolerated with only 2 (5%) patients experiencing grade 3 immune-related adverse events. The addition of IDO-inhibitor augmented rates of pTR in patients with high baseline IDO RNA expression (p<0.05). Response-adaptive surgical timing demonstrated reliability in differentiating pathologic responders versus non-responders (p=0.009). A pretreatment NK cell signature, PD-L1 status, and IFN-g expression in the HPV– cohort correlated with response. HPV+ cohort found B-cell and CAF signatures predictive of response/non-response. Conclusions: Response-adaptive surgical timing enhanced treatment response. IDO-inhibitor BMS986205 augmented pTR in patients with high IDO1-expression in baseline samples, indicating a need for identifying and targeting resistant nodes to immunotherapy. HPV-status-dependent signatures predicting response to immunotherapy in HNSCC warrant further study.
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Project description:We profiled 70,781 peripheral immune cells taken before, during, and after treatment with chemotherapy and immunotherapy of patients with advanced gastrointestinal cancers using single cell RNA sequencing. Prior to therapy, responders had a higher relative abundance of undifferentiated (naïve) CD4+ T cells, while non-responders had more differentiated CD4+ and CD8+ effector memory (EM) cells. Further, the EM cells present in responders were exhausted, suggesting prior recognition of tumor. Upon anti-PD-1 treatment, T cells of responders showed a shift towards increased differentiation and a higher relative abundance of cytotoxic CD8+ T cells than non-responders, with both populations and monocytes showing striking activation of interferon and MHC processing pathways. In addition to T cells, responders were enriched in classical monocytes prior to therapy, with a predominance of high TNF-α and growth factor activity associated with inhibition of NF-κB. The number and signaling activation states of T cells and classical monocytes, as well as their evolution soon after the initiation of therapy, may be predictive markers of immunotherapy response.
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