Tissue‐specific tumor microenvironments influence responses to immunotherapies

Abstract

Objectives Investigation of variable response rates to cancer immunotherapies has exposed the immunosuppressive tumor microenvironment (TME) as a limiting factor of therapeutic efficacy. A determinant of TME composition is the tumor location, and clinical data have revealed associations between certain metastatic sites and reduced responses. Preclinical models to study tissue‐specific TMEs have eliminated genetic heterogeneity, but have investigated models with limited clinical relevance. Methods We investigated the TMEs of tumors at clinically relevant sites of metastasis (liver and lungs) and their impact on αPD‐1/αCTLA4 and trimAb (αDR5, α4‐1BB, αCD40) therapy responses in the 67NR mouse breast cancer and Renca mouse kidney cancer models. Results Tumors grown in the lungs were resistant to both therapies whereas the same tumor lines growing in the mammary fat pad (MFP), liver or subcutaneously could be completely eradicated, despite greater tumor burden. Assessment of tumor cells and drug delivery in 67NR lung or MFP tumors revealed no differences and prompted investigation into the immune TME. Lung tumors had a more immunosuppressive TME with increased myeloid‐derived suppressor cell infiltration, decreased T cell infiltration and activation, and decreased NK cell activation. Depletion of various immune cell subsets indicated an equivalent role for NK cells and CD8+ T cells in lung tumour control. Thus, targeting T cells with αPD‐1/αCTLA4 or trimAb was not sufficient to elicit a robust antitumor response in lung tumors. Conclusion Taken together, these data demonstrate that tissue‐specific TMEs influence immunotherapy responses and highlight the importance in defining tissue‐specific response patterns in patients.

Identification of CXCL8 as an Immune Microenvironment Regulator of Colorectal Cancer: A Bioinformatics Study Based on Cancer Genome Atlas and Gene Expression Omnibus Datasets

“…In this study, we rst indicated that CXCL8 upregulation is negatively associated with CD8 + T cell immune in ltration in CRC. Moreover, evidence showed that a series of molecular features in uenced immunotherapy e cacy, including expression of immune checkpoint molecules [33], in ltration of CD8 + T cell [35,36], oncogenic pathways [37], and tumor-speci c neoantigens [38]. In this study, we found that CXCL8 up-regulation is negatively associated with PD-L1 (CD274) and PD-L2 (PDCD1LG2) Meanwhile, we established that the high expression of CXCL8 was positively correlated with the HIF-1α expression.…”

Exploration of the personalized immune checkpoint atlas of plasma cell dyscrasias patients using high‑dimensional single‑cell analysis

“…leukocytes that regulate T lymphocyte activation and effector functions (17,18). These immune regulatory checkpoints play critical roles in the maintenance of self-tolerance and immune homeostasis under normal physiological conditions; however, cancer cells co-opt these checkpoints to escape immune attack (19,20). Nevertheless, blocking inhibitory receptors can enlist and strengthen the immune system to attack tumors and has achieved clinical success in treating many tumor types, even metastatic and chemo-resistant cancer (21)(22)(23)(24).…”

Primary and metastatic breast tumors cross-talk to influence immunotherapy responses

“…Tumor tissues were harvested, stained, and analyzed as previously described. 20 The following antibodies were used: CD3 BV605 (Biolegend, 17A2), CD4 BUV805 (BD, GK1.5), CD8 BUV737 (BD, 53-6.7), CD11b BV711 (Biolegend, M1/70), CD11c BV785 (Biolegend, N418), CD19 BV785 (BD, 6D5), CD27 APC (BD, LG.7F9), CD44 FITC (BD, 1M7), CD45.2 APC Cy7 (eBioscience, 104), CD49b FITC (BD, DX5), CD62L BV785 (Biolegend, MEL-14), CD69 PE Cy7 (Biolegend, H1.2F3), CD103 PE (Biolegend, 2E7), CD206 FITC (Biolegend, C068C2), CTLA4 PE (BD, UC10-4F10-11), FoxP3 e450 (eBioscience, FJK16S), F4/80 BV421 (BD, T45-2342), IFNγ APC (Biolegend, XMG1.2), Ly6C PE Cy7 (Biolegend, HK1.4), Ly6G BV605 (Biolegend, 1A8), MHCII APC (eBioscience, M5/ 144.15.2), PD-1 BUV395 (BD, J43), TNFα Pacific Blue (Biolegend, MP6-XT22) and the viability dye Fixable Yellow (Invitrogen).…”

“…We previously demonstrated disparate TMEs and immunotherapy responses in 67NR MFP and lung tumors. 20 Therefore, use of this model was ideal to investigate whether cross-talk between primary and metastatic tumors can influence immunotherapy responses.…”

“…We previously found that breast tumors grown in the lungs of mice were less responsive to αPD-1/αCTLA4 and an agonist antibody treatment trimAb (αDR5, αCD40, and α4-1BB) compared to tumors grown elsewhere. 20 Comparisons between 67NR lung and mammary fat pad (MFP) tumors revealed that these tumors had distinct TMEs and differences in the immune cells required for tumor control. The current study aimed to investigate potential cross-talk between tumors in different locations when present simultaneously to more accurately represent metastatic disease.…”