In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival

Abstract

Accumulating preclinical evidence suggests that anticancer immune responses contribute to the success of chemotherapy. However, the predictive value of tumour-infiltrating lymphocytes after neoadjuvant chemotherapy for breast cancer remains unknown. We hypothesized that the nature of the immune infiltrate following neoadjuvant chemotherapy would predict patient survival. In a series of 111 consecutive HER2- and a series of 51 non-HER2-overexpressing breast cancer patients treated by neoadjuvant chemotherapy, we studied by immunohistochemistry tumour infiltration by FOXP3 and CD8 T lymphocytes before and after chemotherapy. Kaplan-Meier analysis and Cox modelling were used to assess relapse-free survival (RFS) and overall survival (OS). A predictive scoring system using American Joint Committee on Cancer (AJCC) pathological staging and immunological markers was created. Association of high CD8 and low FOXP3 cell infiltrates after chemotherapy was significantly associated with improved RFS (p = 0.02) and OS (p = 0.002), and outperformed classical predictive factors in multivariate analysis. A combined score associating CD8/FOXP3 ratio and pathological AJCC staging isolated a subgroup of patients with a long-term overall survival of 100%. Importantly, this score also identified patients with a favourable prognosis in an independent cohort of HER2-negative breast cancer patients. These results suggest that immunological CD8 and FOXP3 cell infiltrate after treatment is an independent predictive factor of survival in breast cancer patients treated with neoadjuvant chemotherapy and provides new insights into the role of the immune milieu and cancer.

Polyfunctional response by ImmTAC (IMCgp100) redirected CD8+ and CD4+ T cells

“…Additionally, the cytokines and chemokines released by IMCgp100 redirected T cells are strong attractants of a multitude of other immune cells. The density of tumour‐infiltrating lymphocytes has been shown to be predictive of patient survival for a number of different tumours 37, 38, 39, 40…”

Density of Tumor-Infiltrating FOXP3+ T Cells as a Response Marker for Induction Chemoradiotherapy and a Potential Prognostic Factor in Patients Treated with Trimodality Therapy for Locally Advanced Non-Small Cell Lung Cancer

“…High CD8+ T cell densities in the tumor stroma of patients with breast cancer who underwent neoadjuvant chemotherapy 13) and in the peripheral blood of patients with advanced NSCLC after platinum-based chemotherapy were reported to be a favorable prognostic marker. 27) Some reports have demonstrated experimentally that radiation can induce CD8+ T cell-mediated antitumor immune reactions.…”

“…In breast cancer patients treated with neoadjuvant chemotherapy, low infiltration of FOXP3+ Tregs with or without high CD8+ T cells was reported to be highly associated with good pathological response 11) or favorable prognosis. 12,13) Low FOXP3+ Treg density in the tumor stroma of ovarian cancer patients treated with neoadjuvant chemotherapy 14) or in the tumor-draining lymph nodes of patients with cervical cancer who underwent induction CRT 15) was also shown to be a favorable prognostic factor. To date, the effects of CRT on tumor-infiltrating T cells in patients with NSCLC are largely unknown.…”

Consensus guidelines for the detection of immunogenic cell death

“…Thus, the relative abundance of tumor-infiltrating CD8 C cytotoxic T lymphocytes (CTLs) and CD4 C CD25 C FOXP3 C regulatory T cells reportedly predicts the propensity of breast carcinoma patients to benefit from anthracycline-or oxaliplatin-based chemotherapy, respectively. 52,120 Along similar lines, single nucleotide polymorphisms in the genes coding for ICD-relevant receptors such as Toll-like receptor 4 (TLR4) and purinergic receptor P2X, ligand-gated ion channel, 7 (P2RX7) have been shown to influence disease outcome among breast carcinoma patients treated with anthracycline-based chemotherapy. 41,119 Taken together, these observations demonstrate that the induction of ICD is a therapeutically relevant objective, calling for the identification of novel ICD inducers and molecules that improve the immunogenicity of conventional variants of apoptosis.…”