Chemotherapy induces enrichment of CD47 ⁺ /CD73 ⁺ /PDL1 ⁺ immune evasive triple-negative breast cancer cells

Abstract

Triple-negative breast cancer (TNBC) is treated with cytotoxic chemotherapy and is often characterized by early relapse and metastasis. To form a secondary (recurrent and/or metastatic) tumor, a breast cancer cell must evade the innate and adaptive immune systems. CD47 enables cancer cells to evade killing by macrophages, whereas CD73 and PDL1 mediate independent mechanisms of evasion of cytotoxic T lymphocytes. Here, we report that treatment of human or murine TNBC cells with carboplatin, doxorubicin, gemcitabine, or paclitaxel induces the coordinate transcriptional induction of CD47, CD73, and PDL1 mRNA and protein expression, leading to a marked increase in the percentage of CD47CD73PDL1 breast cancer cells. Genetic or pharmacological inhibition of hypoxia-inducible factors (HIFs) blocked chemotherapy-induced enrichment of CD47CD73PDL1 TNBC cells, which were also enriched in the absence of chemotherapy by incubation under hypoxic conditions, leading to T cell anergy or death. Treatment of mice with cytotoxic chemotherapy markedly increased the intratumoral ratio of regulatory/effector T cells, an effect that was abrogated by HIF inhibition. Our results delineate an HIF-dependent transcriptional mechanism contributing to TNBC progression and suggest that combining chemotherapy with an HIF inhibitor may prevent countertherapeutic induction of proteins that mediate evasion of innate and adaptive antitumor immunity.

Anti‐tumour immune response in GL261 glioblastoma generated by Temozolomide Immune‐Enhancing Metronomic Schedule monitored with MRSI‐based nosological images

“…This result brings us significant insight for future research in preclinical GL261 GB, indicating that anti‐PD‐1 immunotherapy should be more effective as second line treatment in late relapsing GL261 tumours, while combined TMZ and kinase inhibitors such as CX‐4945 may be best for fast growth, “non‐responding” GL261 tumours. In addition, kinase inhibitors could contribute an added value through another pathway, impairing hypoxia‐inducible factor (HIF) stabilization which in turn could lead to decrease of PD‐L1 content . These hypotheses are amenable to test in future work and can lead to further improvement of the outcome of tumour‐bearing mice.…”

“…In addition, kinase inhibitors could contribute an added value through another pathway, impairing hypoxia-inducible factor (HIF) stabilization which in turn could lead to decrease of PD-L1 content. 40 These hypotheses are amenable to test in future work and can lead to further improvement of the outcome of tumour-bearing mice.…”

Predictive and prognostic value of PDL1 protein expression in breast cancer patients in neoadjuvant setting

“…Of note, PDL1-as a molecule that involved in tumor immune escape-is thought to indicate a poor over all survival in many tumors [7][8][9][10][11][12] . The mechanism is generally thought to be related to a PDL1-mediated T-killer cell apoptosis and T-regulatory cell differentiation 5,23 . Nevertheless, laboratory experiments showed that chemotherapy could induce the expression of PDL1 and other immune escape-associated molecules (CD47, CD73, etc.)…”

Chemotherapy but not the tumor draining lymph nodes determine the immunotherapy response in secondary tumors

“…Combinations of chemotherapies with immunotherapies are widely discussed and currently tested in pre-clinical models and clinical trials 17,[35][36][37] . Mechanistically, chemotherapy can promote anti-tumor immunity via inducing immunogenic cell death and disrupting tumor microenvironment components that are used to evade the immune response [38][39][40][41][42] . However, cancer chemotherapies are also considered as immune suppressive due to their cytotoxic effects on immune cells.…”