scholarly journals Influence of Tumor Immune Infiltration on Immune Checkpoint Inhibitor Therapeutic Efficacy: A Computational Retrospective Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Rong Liu ◽  
Fang Yang ◽  
Ji-Ye Yin ◽  
Ying-Zi Liu ◽  
Wei Zhang ◽  
...  

The tumor immune microenvironment (TIME) is likely an important determinant of sensitivity to immune checkpoint inhibitor (ICI) treatment. However, a comprehensive analysis covering the complexity and diversity of the TIME and its influence on ICI therapeutic efficacy is still lacking. Data from 782 samples from 10 ICI clinical trials were collected. To infer the infiltration of 22 subsets of immune cells, CIBERSORTx was applied to the bulk tumor transcriptomes. The associations between each cell fraction and the response to ICI treatment, progression-free survival (PFS) and overall survival (OS) were evaluated, modeling cellular proportions as quartiles. Activity of the interferon-γ pathway, the cytolytic activity score and the MHC score were associated with good prognosis in melanoma. Of the immune cells investigated, M1 macrophages, activated memory CD4+ T cells, T follicular helper (Tfh) cells and CD8+ T cells correlated with response and prolonged PFS and OS, while resting memory CD4+ T cells was associated with unfavorable prognosis in melanoma and urothelial cancer. Consensus clustering revealed four immune subgroups with distinct responses to ICI therapy and survival patterns. The cluster with high proportions of infiltrated CD8+ T cells, activated memory CD4+ T cells, and Tfh cells and low levels of resting memory CD4+ T cells exhibited a higher tumor mutation burden and neoantigen load in melanoma and conferred a higher probability of response and improved survival. Local systemic immune cellular differences were associated with outcomes after ICI therapy. Further investigations of the tumor-infiltrating cellular immune response will lay the foundation for achieving durable efficacy.

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhenyu Yang ◽  
Yulan Deng ◽  
Jiahan Cheng ◽  
Shiyou Wei ◽  
Hao Luo ◽  
...  

BackgroundStratification of patients who could benefit from immune checkpoint inhibitor (ICI) therapy is of much importance. PD-1hiCD8+ T cells represent a newly identified and effective biomarker for ICI therapy response biomarker in lung cancer. Accurately quantifying these T cells using commonly available RNA sequencing (RNA-seq) data may extend their applications to more cancer types.MethodWe built a transcriptome signature of PD-1hiCD8+ T cells from bulk RNA-seq and single-cell RNA-seq (scRNA-seq) data of tumor-infiltrating immune cells. The signature was validated by flow cytometry and in independent datasets. The clinical applications of the signature were explored in non-small-cell lung cancer, melanoma, gastric cancer, urothelial cancer, and a mouse model of breast cancer samples treated with ICI, and systematically evaluated across 21 cancer types in The Cancer Genome Atlas (TCGA). Its associations with other biomarkers were also determined.ResultsSignature scores could be used to identify the PD-1hiCD8+ T subset and were correlated with the fraction of PD-1hiCD8+ T cells in tumor tissue (Pearson correlation, R=0.76, p=0.0004). Furthermore, in the scRNA-seq dataset, we confirmed the capability of PD-1hiCD8+ T cells to secrete CXCL13, as well as their interactions with other immune cells. In 581 clinical samples and 204 mouse models treated with ICIs, high signature scores were associated with increased survival, and the signature achieved area under the receiver operating characteristic curve scores of 0.755 (ranging from 0.61 to 0.91) in predicting therapy response. In TCGA pan-cancer datasets, our signature scores were consistently correlated with therapy response (R=0.78, p<0.0001) and partially explained the diverse response rates among different cancer types. Finally, our signature generally outperformed other mRNA-based predictors and showed improved predictive performance when used in combination with tumor mutational burden (TMB). The signature score is available in the R package “PD1highCD8Tscore” (https://github.com/Liulab/PD1highCD8Tscore).ConclusionThrough estimating the fraction of the PD-1hiCD8+ T cell, our signature could predict response to ICI therapy across multiple cancers and could serve as a complementary biomarker to TMB.


2021 ◽  
Vol 9 (6) ◽  
pp. e002181
Author(s):  
Erin F Simonds ◽  
Edbert D Lu ◽  
Oscar Badillo ◽  
Shokoufeh Karimi ◽  
Eric V Liu ◽  
...  

BackgroundGlioblastoma (GBM) is refractory to immune checkpoint inhibitor (ICI) therapy. We sought to determine to what extent this immune evasion is due to intrinsic properties of the tumor cells versus the specialized immune context of the brain, and if it can be reversed.MethodsWe used CyTOF mass cytometry to compare the tumor immune microenvironments (TIME) of human tumors that are generally ICI-refractory (GBM and sarcoma) or ICI-responsive (renal cell carcinoma), as well as mouse models of GBM that are ICI-responsive (GL261) or ICI-refractory (SB28). We further compared SB28 tumors grown intracerebrally versus subcutaneously to determine how tumor site affects TIME and responsiveness to dual CTLA-4/PD-1 blockade. Informed by these data, we explored rational immunotherapeutic combinations.ResultsICI-sensitivity in human and mouse tumors was associated with increased T cells and dendritic cells (DCs), and fewer myeloid cells, in particular PD-L1+ tumor-associated macrophages. The SB28 mouse model of GBM responded to ICI when grown subcutaneously but not intracerebrally, providing a system to explore mechanisms underlying ICI resistance in GBM. The response to ICI in the subcutaneous SB28 model required CD4 T cells and NK cells, but not CD8 T cells. Recombinant FLT3L expanded DCs, improved antigen-specific T cell priming, and prolonged survival of mice with intracerebral SB28 tumors, but at the cost of increased Tregs. Targeting PD-L1 also prolonged survival, especially when combined with stereotactic radiation.ConclusionsOur data suggest that a major obstacle for effective immunotherapy of GBM is poor antigen presentation in the brain, rather than intrinsic immunosuppressive properties of GBM tumor cells. Deep immune profiling identified DCs and PD-L1+ tumor-associated macrophages as promising targetable cell populations, which was confirmed using therapeutic interventions in vivo.


2021 ◽  
Author(s):  
Laura Kist de Ruijter ◽  
Pim P. van de Donk ◽  
Jahlisa S. Hooiveld-Noeken ◽  
Danique Giesen ◽  
Alexander Ungewickell ◽  
...  

2019 ◽  
Vol 70 (1) ◽  
pp. e19-e20
Author(s):  
Cathrin L.C. Gudd ◽  
Tong Liu ◽  
Evangelos Triantafyllou ◽  
David J. Pinato ◽  
You Yone ◽  
...  

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9606-9606
Author(s):  
Sujay Yogesh Shah ◽  
Jonathon Joseph Vallejo ◽  
Yutao Gong ◽  
Thomas D. Brown ◽  
Chenan Zhang ◽  
...  

9606 Background: Higher PD-L1 score ≥ 50% predicts for greater benefit to immune checkpoint inhibitor (ICI) therapy in first line (1L) treatment of aNSCLC. It has recently been reported that PD-L1 score ≥ 90% predicts for even greater benefit to 1L ICI monotherapy (Aguilar et al., 2019). We examined pooled clinical trial databases to examine the relationship between high PD-L1 expression across multiple ICI monotherapies in 1L and second line (2L) treatment of aNSCLC. Methods: Data was pooled from trials (five 1L and five 2L) of ICI for the treatment of patients with aNSCLC. We defined PD-L1 score as the proportion of tumor cell stained by the assay (total of four assays identified) and included patients in the analysis with PD-L1 score ≥ 50%. Tumor-infiltrating immune cell staining was not considered. Progression-free survival (PFS) and overall survival (OS) by line of therapy for patients with PD-L1 score ≥ 90% and patients with PD-L1 score 50-89% was analyzed. Results: A total of 1320 patients treated with ICI monotherapy were identified, 873 in 1L and 447 in 2L. Median follow-up was 9.6 months in 2L patients and 13.3 months in 1L patients. Patients receiving 2L ICI therapy with PD-L1 score ≥ 90% (N = 208) had longer PFS and OS compared to patients with PD-L1 score 50-89% (N = 239), with mPFS 7.1 vs. 4.2 months (HR = 0.66 [95% CI: 0.52-0.83]) and mOS NR vs. 15.8 months (HR = 0.66 [95% CI: 0.49-0.89]). 1L ICI therapy analysis revealed similar trends, as patients with PD-L1 score ≥ 90% (N = 405) had longer PFS and OS compared to patients with a PD-L1 score 50-89% (N = 468), with mPFS 8.3 vs. 5.4 months (HR = 0.78 [95% CI: 0.66-0.92]) and mOS 22.9 vs. 16.4 months (HR = 0.74 [95% CI: 0.61-0.90]). Conclusions: This analysis showed the potential of an enhanced clinical benefit in patients with aNSCLC and PD-L1 score ≥90% across ICI monotherapies in both the 1L and 2L treatment setting. These data will be further analyzed in real world populations.


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