Immunotherapy in colorectal cancer: for the select few or all?

Arora, Sukeshi Patel; Mahalingam, Devalingam

doi:10.21037/jgo.2017.06.10

Cited by 56 publications

(50 citation statements)

References 60 publications

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“…The GDC‐0919 and epacadostat molecules are among the anti‐IDO agents in clinical trials. GDC‐0919 is in Phase 1 clinical development (NCT 02048709) (Arora & Mahalingam, 2018; Takamatsu et al, 2015), whereas the combination of epacadostat and pembrolizumab and azacitidine is studied in a Phase I/II study with an expansion cohort in MSS CRC (NCT02959437) (Arora & Mahalingam, 2018). TIM‐3 contributes to the exhaustion of CD8+ T cells and plays a coinhibitory role parallel to PD‐1 and CTLA‐4 in the immune system.…”

Section: Immunotherapy Of Colorectal Cancer By Focusing On Pd‐1/pd‐l1mentioning

confidence: 99%

“…The GDC-0919 and epacadostat molecules are among the anti-IDO agents in clinical trials. GDC-0919 is in Phase 1 clinical development (NCT 02048709) (Arora & Mahalingam, 2018;Takamatsu et al, 2015), whereas the combination of epacadostat and pembrolizumab and azacitidine is studied in a Phase I/II study with an expansion cohort in MSS CRC (NCT02959437) (Arora & Mahalingam, 2018 Currently, MSI is considered as a well-known biomarker for PD-1 blockade. This overexpression is the logic behind the enhanced responsiveness of MMR-d CRC for anti-PD-1 therapies.…”

Section: Immunotherapy Of Colorectal Cancer By Focusing On Pd-1/pd-l1mentioning

confidence: 99%

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PD‐1/PD‐L1‐dependent immune response in colorectal cancer

Payandeh

Khalili

Somi

et al. 2020

Journal Cellular Physiology

101

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Colorectal cancer (CRC) is still considered as the third most frequent cancer in the world. Microsatellite instability (MSI), inflammation, and microRNAs have been demonstrated as the main contributing factors in CRC. Subtype 1 CRC is defined by NK cells infiltration, induction of Th1 lymphocyte and cytotoxic T cell responses as well as upregulation of immune checkpoint proteins including programmed cell death‐1 (PD‐1). Based on the diverse features of CRC, such as the stage and localization of the tumor, several treatment approaches are available. However, the efficiency of these treatments may be decreased due to the development of diverse resistance mechanisms. It has been proven that monoclonal antibodies (mAbs) can increase the effectiveness of CRC treatments. Nowadays, several mAbs including nivolumab and pembrolizumab have been approved for the treatment of CRC. Immune checkpoint receptors including PD‐1 can be inhibited by these antibodies. Combination therapy gives an opportunity for advanced treatment for CRC patients. In this review, an update has been provided on the molecular mechanisms involved in MSI colorectal cancer immune microenvironment by focusing on PD‐ligand 1 (PD‐L1) and treatment of patients with advanced immunotherapy, which were examined in the different clinical trial phases. Considering induced expression of PD‐L1 by conventional chemotherapeutics, we have summarized the role of PD‐L1 in CRC, the chemotherapy effects on the PD‐1/PD‐L1 axis and novel combined approaches to enhance immunotherapy of CRC by focusing on PD‐L1.

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Section: Immunotherapy Of Colorectal Cancer By Focusing On Pd‐1/pd‐l1mentioning

confidence: 99%

Section: Immunotherapy Of Colorectal Cancer By Focusing On Pd-1/pd-l1mentioning

confidence: 99%

PD‐1/PD‐L1‐dependent immune response in colorectal cancer

Payandeh

Khalili

Somi

et al. 2020

Journal Cellular Physiology

101

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“…Melanoma and colorectal cancer (CRC) are common cancers associated with high mortality worldwide . The management of melanoma and CRC have improved overall survival rates during the last decades, yet the majority of patients do not respond to treatment and succumb to disease progression, mainly due to upregulating the surface program death‐ligand 1 (PD‐L1) expression . Therefore, deep understanding of the PD‐L1 upregulating mechanism is urgently needed for melanoma and CRC.…”

Section: Introductionmentioning

confidence: 99%

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

Zhou

Zhang

et al. 2019

Intl Journal of Cancer

146

131

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Cancer‐associated fibroblasts (CAFs) play a key role in orchestrating the tumor malignant biological properties within tumor microenvironment and evidences demonstrate that CAFs are a critical regulator of tumoral immunosuppression of the T cell response. However, the functions and regulation of CAFs in the expression of programmed death‐ligand 1 (PD‐L1) in melanoma and colorectal carcinoma (CRC) are not completely understood. Herein, by scrutinizing the expression of α‐SMA and PD‐L1 in melanoma and CRC tissues, we found that CAFs was positive correlated with PD‐L1 expression. Further analyses showed that CAFs promoted PD‐L1 expression in mice tumor cells. By detecting a majority of cytokines expression in normal mice fibroblasts and CAFs, we determined that CXCL5 was abnormal high expression in CAFs and the immunohistochemistry and in situ hybridization confirmed that were CAFs which were expressing CXCL5. In addition, CXCL5 promoted PD‐L1 expression in B16, CT26, A375 and HCT116. The silencing of CXCR2, the receptor of CXCL5, inhibited the PD‐L1 expression induced by CAFs in turn. Functionally, CXCL5 derived by CAFs promoted PD‐L1 expression in mice tumor cells through activating PI3K/AKT signaling. LY294002, the inhibitor of PI3K, confirmed that CXCL5 forested an immunosuppression microenvironment by promoting PD‐L1 expression via PI3K/AKT signaling. Meanwhile, the B16/CT26 xenograft tumor models were used and both CXCR2 and p‐AKT were found to be positively correlated with PD‐L1 in the xenograft tumor tissues. The immunosuppressive action of CAFs on tumor cells is probably reflective of them being a potential therapeutic biomarker for melanoma and CRC.

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“…This interaction between chemotherapy and immune pathway in cancer is of great interest due to the success of immunotherapy for different tumor types. These data could contribute to improving the clinical use of the novel immune checkpoint inhibitors (i.e., anti-programmed cell death protein 1, PD-1) ( Toh et al, 2016 ; Passardi et al, 2017 ; Arora and Mahalingam, 2018 ) by suggesting a potential synergism between immunotherapy and the traditional chemotherapeutics ( Van Der Kraak et al, 2016 ; Di Franco et al, 2017 ; Emambux et al, 2018 ). In this context, the discovery of novel markers that predict the impact of chemotherapy on tumor immunity could be important for selecting patients who could benefit from immune modulators in combination with anticancer agents.…”

Section: Discussionmentioning

confidence: 99%

A Clinical-Genetic Score to Identify Surgically Resected Colorectal Cancer Patients Benefiting From an Adjuvant Fluoropyrimidine-Based Therapy

et al. 2018

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There are clinical challenges related to adjuvant treatment in colorectal cancer (CRC) and novel molecular markers are needed for better risk stratification of patients. Our aim was to integrate our previously reported clinical-genetic prognostic score with new immunogenetic markers of 5-year disease-free survival (DFS) to evaluate the recurrence risk stratification before fluoropyrimidine (FL)-based adjuvant therapy. The study population included a total of 270 stage II-III CRC patients treated with adjuvant FL with (FL + OXA, n = 119) or without oxaliplatin (FL, n = 151). Patients were genotyped for a panel of 192 tagging polymorphisms in 34 immune-related genes. The IFNG-rs1861494 polymorphism was associated with worse DFS in the FL + OXA (HR = 2.14, 95%CI 1.13–4.08; P = 0.020, q-value = 0.249) and FL (HR = 1.97, 95%CI 1.00–3.86; P = 0.049) cohorts, according to a dominant model. The integration of IFNG-rs1861494 in our previous clinical genetic multiparametric score of DFS improved the patients’ risk stratification (Log-rank P = 0.0026 in the pooled population). These findings could improve the discrimination of patients who would benefit from adjuvant treatment. In addition, the results may help better elucidate the interplay between the immune system and chemotherapeutics and help determine the efficacy of anti-tumor strategies.

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Immunotherapy in colorectal cancer: for the select few or all?

Cited by 56 publications

References 60 publications

PD‐1/PD‐L1‐dependent immune response in colorectal cancer

PD‐1/PD‐L1‐dependent immune response in colorectal cancer

Cancer‐associated fibroblasts promote PD‐L1 expression in mice cancer cells via secreting CXCL5

A Clinical-Genetic Score to Identify Surgically Resected Colorectal Cancer Patients Benefiting From an Adjuvant Fluoropyrimidine-Based Therapy

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