Tumour budding and CD8+ T‐cells: “attackers” and “defenders” in rectal cancer with and without neoadjuvant chemoradiotherapy

BackgroundDistant metastasis is the major cause of mortality in patients with locally advanced rectal cancer (LARC) following neoadjuvant chemoradiotherapy. Local radiotherapy can trigger an abscopal response to metastatic tumor cells. However, the abscopal effect is a rare event. CD4+ regulatory T (Treg) cell is a highly immune-suppressive subset which impedes immune surveillance against cancer, prevents the development of effective antitumor immunity and promotes tumor progression. We assume that the exploitation of the proimmunogenic effects of radiotherapy with anti-CD25 or anti-Cytotoxic T-Lymphocyte Associated Protein 4 (anti-CTLA4) monoclonal antibodies (mAbs) may enhance the local and abscopal effects in rectal cancer and improve the therapeutic outcome.MethodsmRNA expression profiling of 81 pretreatment biopsy samples from LARC patients who received neoadjuvant radiotherapy (nRT) was performed to analyze the correlation between gene expression and prognosis. A retrospective analysis of patients with rectal cancer with distant metastasis or synchronous extracolonic cancers was performed to evaluate the abscopal effect of radiotherapy on rectal cancer. Two different dual-tumor mouse models were established to investigate the efficacy of single dose and dose-fractionated radiotherapy combined with anti-CD25 or anti-CTLA4 and anti-Programmed cell death 1 ligand 1 (anti-PD1) mAbs on the local tumor growth and liver metastasis. The univariate Cox regression analysis, one-way analysis of variance, Dunnett’s test, a mixed-effect linear model and Kaplan-Meier survival analysis were used to calculate p values.ResultsThe proportion of Tregs in pre-nRT biopsies was negatively correlated with prognosis (p=0.007). The retrospective analysis showed that regressing liver metastases were infiltrated by CD8+ T cells. In contrast, stable/progressing metastases and synchronous extracolonic cancers were characterized by PD1+ T cells and Tregs infiltration. Animal experiment results demonstrated that the combination of radiotherapy and anti-CD25/CTLA4 mAb resulted in a significant increase in CD8+ T cells and CD8+/CD4+ ratio in primary and secondary tumors compared with the irradiation alone group (all p<0.05 or p<0.01). The combined treatment was able to decrease Tregs, PD1+CD8+ and PD1+CD4+ T cells (p<0.05), suppress locally irradiated and distal unirradiated tumor growth, and improve overall survival rate. Radiotherapy in conjunction with anti-CTLA4 reduced liver metastasis (p<0.05).ConclusionsThese data indicated that radiotherapy plus depletion of Tregs was able to improve the antitumor response and generate an abscopal effect.

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Tumor-Infiltrating Cytotoxic T Cells and Tumor-Associated Macrophages Correlate With the Outcomes of Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer

Frontiers in Oncology ◽

10.3389/fonc.2021.743540 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yuqin Yang ◽

Wenjing Tian ◽

Liqian Su ◽

Peiqiu Li ◽

Xiaohua Gong ◽

...

Keyword(s):

Rectal Cancer ◽

T Cells ◽

Clinical Outcomes ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer ◽

Clinicopathological Parameters ◽

Validation Group ◽

Tumor Associated Macrophages

BackgroundTumor-infiltrating immune cells (TIICs) play a key role in immunoregulatory networks and are related to tumor development. Emerging evidence shows that these cells are associated with sensitivity to chemotherapy and radiotherapy. However, the predictive role of TIICs in the outcomes of neoadjuvant chemoradiotherapy (nCRT) for locally advanced rectal cancer (LARC) is unclear.MethodsImaging mass cytometry (IMC) was performed to comprehensively assess the immune status before nCRT in 6 patients with LARC (3 achieved pathological complete response (pCR), 3 did not) with matched clinicopathological parameters. Immunohistochemistry (IHC) for CD8, CD163 and Foxp3 on biopsy samples from 70 patients prior to nCRT and logistic regression analysis were combined to further evaluate its predictive value for treatment responses in an independent validation group.ResultsA trend of increased CD8+ cytotoxic T lymphocytes (CTLs) and decreased CD163+ tumor-associated macrophages (TAMs) and Foxp3+ regulatory T cells (Tregs) in the pCR group was revealed by IMC. In the validation group, CTLs and TAMs were strong predictors of the clinical response to nCRT. High levels of CTLs were positively associated with the pCR ratio (OR=1.042; 95% CI: 1.015~1.070, p=0.002), whereas TAMs were correlated with a poor response (OR=0.969; 95% CI: 0.941~0.998, p=0.036). A high density of TAMs was also associated with an advanced cN stage.ConclusionCTLs in the tumor microenvironment (TME) may improve the response to nCRT, whereas TAMs have the opposite effect. These results suggest that these cells might be potential markers for the clinical outcomes of nCRT and aid in the clinical decision-making of LARC for improved clinical outcomes.

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Peripheral blood CD45RO+T cells is a predictor of the effectiveness of neoadjuvant chemoradiotherapy in locally advanced rectal cancer

Medicine ◽

10.1097/md.0000000000026214 ◽

2021 ◽

Vol 100 (25) ◽

pp. e26214

Author(s):

Zhiwei Zhai ◽

Zhenjun Wang ◽

Mulan Jin ◽

Kunning Zhang

Keyword(s):

Rectal Cancer ◽

T Cells ◽

Peripheral Blood ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Advanced Rectal Cancer ◽

Locally Advanced Rectal Cancer

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672 The effect of chemoradiotherapy and tumor histology on the immune contexture of tumor-draining lymph nodes in NSCLC

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.672 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A700-A700

Author(s):

Marieke Fransen ◽

Famke Schneiders ◽

Vinitha Kandiah ◽

Teodora Radonic ◽

Idris Bahce ◽

...

Keyword(s):

T Cells ◽

Lymph Nodes ◽

Cd8 T Cells ◽

Standard Treatment ◽

Neoadjuvant Chemoradiotherapy ◽

Combinatorial Design ◽

Current Standard ◽

Tumor Histology ◽

Immune Contexture ◽

Draining Lymph Nodes

BackgroundRecently, the concept of locally delivered immune modulatory agents (re-)invigorating sub-optimally primed tumor-specific T cells and lifting suppression in the tumor microenvironment (TME) and tumor-draining lymph nodes (TDLN) has gained attention. TDLN play an important role in the induction of tumor-specific effector T cells. It is here that specialized dendritic cell (DC) subsets present tumor-derived antigens to naïve T cells and start effective adaptive immune responses to cancer. Unfortunately, TDLN are also rapidly targeted by tumors for immune suppression, which may impair the efficacy of immunotherapy. Currently, there is limited knowledge on the immune contexture of TDLN in non-small cell lung cancer (NSCLC), differences between types of tumor histology, and the influence of standard treatment.MethodsIn an exploratory study, we collected and analyzed viable cells from TDLN from patients with NSCLC, scheduled for surgical resection. To date, we have analyzed 43 TDLN from a total of 10 patients with multiparameter flowcytometry panels, either untreated or after neoadjuvant chemoradiotherapy (nCRT).ResultsOur analyses reveal differences between squamous cell carcinoma (SCC) and adenocarcinoma (AC), discernable even within this small cohort. In AC, higher levels of PD-L1 on CD11c+CD1c- LN-resident macrophages and CD1a+ migratory DC were accompanied by a lower activation state of CD8+ T cells by PD-1, CTLA-4 and CD69 expression levels. Furthermore, we found decreased activation of LN-resident DCs (by PD-L1 and CD83 levels) and a striking decrease in PD-1 and CD69 on CD8+ T cells, a decrease in effector and central memory CD8+ T cells, and an increase in naïve CD8+ T cells and Treg subsets after nCRT treatment, the current standard treatment of stage III NSCLC patients.ConclusionsThese AC/SCC –related differences and nCRT-induced alterations in the immune status of hold clues for future patient stratification and combinatorial design of CRT with immunotherapy.Ethics ApprovalThis study was approved by the Medical Ethics Committee; 2017.545

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