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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2022-07-07 | GSE200996 | GEO
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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Project description:Immunotherapy, such as anti-PD1, has improved the survival of patients with metastatic melanoma; However, predicting which patients will respond to immunotherapy is still unknown. In this study we analyzed pre-immunotherapy treated tumors from 52 patients with metastatic melanoma and monitored their response based on RECIST 1.1 criteria. The responders group contained 21 patients that had a complete or partial response, while the 31 non-responders had stable or progressive disease. Whole exome sequencing (WES) was used to identify biomarkers of anti-PD1 response from somatic mutations between the two groups. Variants in codons G34 and G41 in NFKBIE, a negative regulator of NF-kB, were found exclusively in the responders. NKBIE-related genes within the responder group were also enriched compared to the non-responders. Patients that harbored NFKBIE-related gene mutations also had a higher mutational burden, decreased tumor volume with treatment, and increased progression-free survival. RNA sequencing on a subsection of tumor samples identified differential expression of the TNFA signaling via NFKB pathway, which includes CD83. By overexpressing NFKBIEG34E we were able to demonstrate this mutation is related to increased NF-kB activity, including increased CD83 protein expression when compared with the wildtype. These results suggest that increased NF-kB signaling as a consequence of an NFKBIE mutation may contribute to a favorable anti-PD1 treatment response, including a possible novel role of CD83 in solid tumors.
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2021-06-03 | GSE175737 | GEO
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