Predictive biomarkers of colon cancer immunotherapy: Present and future

Hou, Wanting; Yi, Cheng; Zhu, Hong

doi:10.3389/fimmu.2022.1032314

Cited by 60 publications

(47 citation statements)

References 191 publications

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“…Future studies will further investigate this topic by evaluating tumor-infiltrating lymphocytes and CXCL14 expression in the tumor microenvironment, especially comparing CDX-2 positive cases with CDX-2 negative cases. It will also be interesting to evaluate PD-L1 expression in CDX2-positive and -negative patients and see if the lack of correlation with response to immunotherapy in mCRC, as described by other works 6,44,46,78 , is confirmed.…”

Section: Discussionmentioning

confidence: 79%

CDX-2 expression correlates with clinical outcomes in MSI-H metastatic colorectal cancer patients receiving immune checkpoint inhibitors

Ziranu

Pretta

Pozzari

et al. 2023

Sci Rep

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Immune checkpoint inhibitors (ICIs) showed efficacy in metastatic colorectal cancer (mCRC) with mismatch-repair deficiency or high microsatellite instability (dMMR-MSI-H). Unfortunately, a patient’s subgroup did not benefit from immunotherapy. Caudal-related homeobox transcription factor 2 (CDX-2) would seem to influence immunotherapy’s sensitivity, promoting the chemokine (C-X-C motif) ligand 14 (CXCL14) expression. Therefore, we investigated CDX-2 role as a prognostic-predictive marker in patients with mCRC MSI-H. We retrospectively collected data from 14 MSI-H mCRC patients treated with ICIs between 2019 and 2021. The primary endpoint was the 12-month progression-free-survival (PFS) rate. The secondary endpoints were overall survival (OS), PFS, objective response rate (ORR), and disease control rate (DCR). The PFS rate at 12 months was 81% in CDX-2 positive patients vs 0% in CDX-2 negative patients (p = 0.0011). The median PFS was not reached (NR) in the CDX-2 positive group versus 2.07 months (95%CI 2.07–10.8) in CDX-2 negative patients (p = 0.0011). Median OS was NR in CDX-2-positive patients versus 2.17 months (95% Confidence Interval [CI] 2.17–18.7) in CDX2-negative patients (p = 0.026). All CDX-2-positive patients achieved a disease response, one of them a complete response. Among CDX-2-negative patients, one achieved stable disease, while the other progressed rapidly (ORR: 100% vs 0%, p = 0.0005; DCR: 100% vs 50%, p = 0.02). Twelve patients received 1st-line pembrolizumab (11 CDX-2 positive and 1 CDX-2 negative) not reaching median PFS, while two patients (1 CDX-2 positive and 1 CDX-2 negative) received 3rd-line pembrolizumab reaching a median PFS of 10.8 months (95% CI, 10.8–12.1; p = 0.036). Although our study reports results on a small population, the prognostic role of CDX-2 in CRC seems confirmed and could drive a promising predictive role in defining the population more sensitive to immunotherapy treatment. Modulating the CDX-2/CXCL14 axis in CDX-2-negative patients could help overcome primary resistance to immunotherapy.

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Section: Discussionmentioning

confidence: 79%

CDX-2 expression correlates with clinical outcomes in MSI-H metastatic colorectal cancer patients receiving immune checkpoint inhibitors

Ziranu

Pretta

Pozzari

et al. 2023

Sci Rep

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“…However, ICIs are effective in only a small proportion of patients. Multiple attempts are ongoing to enhance their anti-tumor effects [ 24 , 25 ] or determine their efficacy at an early stage with biomarkers using peripheral blood, tissue samples, and imaging modalities [ 26 , 27 , 28 , 29 , 30 , 31 ]. In 2018, Matson et al reported that the patients’ gut microbiome was associated with their response to ICIs [ 32 ].…”

Section: Immune-related Adverse Events (Iraes)mentioning

confidence: 99%

Rheumatic Immune-Related Adverse Events due to Immune Checkpoint Inhibitors—A 2023 Update

Dang¹,

Watanabe²,

Shiomi³

et al. 2023

IJMS

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With the aging of the population, malignancies are becoming common complications in patients with rheumatoid arthritis (RA), particularly in elderly patients. Such malignancies often interfere with RA treatment. Among several therapeutic agents, immune checkpoint inhibitors (ICIs) which antagonize immunological brakes on T lymphocytes have emerged as a promising treatment option for a variety of malignancies. In parallel, evidence has accumulated that ICIs are associated with numerous immune-related adverse events (irAEs), such as hypophysitis, myocarditis, pneumonitis, and colitis. Moreover, ICIs not only exacerbate pre-existing autoimmune diseases, but also cause de novo rheumatic disease–like symptoms, such as arthritis, myositis, and vasculitis, which are currently termed rheumatic irAEs. Rheumatic irAEs differ from classical rheumatic diseases in multiple aspects, and treatment should be individualized based on the severity. Close collaboration with oncologists is critical for preventing irreversible organ damage. This review summarizes the current evidence regarding the mechanisms and management of rheumatic irAEs with focus on arthritis, myositis, and vasculitis. Based on these findings, potential therapeutic strategies against rheumatic irAEs are discussed.

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“…Colorectal cancer (CRC) shows heterogeneous clinical response, and prognostic biomarkers for identifying people at elevated risk of disease recurrence are still underdeveloped [1]. In cases where surgery (and/or neoadjuvant chemoradiation therapy in the rectal cancer setting) may not completely eliminate cancer cells, chemotherapy can be used as adjuvant therapy to reduce the risk of cancer recurrence [2].…”

Section: Introductionmentioning

confidence: 99%

Spatial Effects of Infiltrating T cells on Neighbouring Cancer Cells and Prognosis in Stage III CRC patients

Azimi,

Cho,

Bozkurt

et al. 2024

Preprint

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Colorectal cancer (CRC) is one of the most frequently occurring cancers, but prognostic biomarkers identifying patients at risk of recurrence are still lacking. In this study, we aimed to investigate in more detail the spatial relationship between intratumoural T cells, cancer cells, and cancer cell hallmarks, as prognostic biomarkers in stage III colorectal cancer patients. We conducted multiplexed imaging of 56 protein markers at single cell resolution on resected fixed tissue from stage III CRC patients who received adjuvant 5fluorouracilbased chemotherapy. Images underwent segmentation for tumour, stroma and immune cells, and cancer cell state protein marker expression was quantified at a cellular level. We developed a Python package for estimation of spatial proximity, nearest neighbour analysis focusing on cancer cell T cell interactions at single cell level. In our discovery cohort (MSK), we processed 462 core samples (total number of cells: 1,669,228) from 221 adjuvant 5FU-treated stage III patients. The validation cohort (HV) consisted of 272 samples (total number of cells: 853,398) from 98 stage III CRC patients. While there were trends for an association between percentage of cytotoxic T cells (across the whole cancer core), it did not reach significance (Discovery cohort: p = 0.07, Validation cohort: p = 0.19). We next benchmarked our region-based nearest neighbourhood approach to determine the spatial relationships between cytotoxic T cells, helper T cells and cancer cell clusters. In the both cohorts, we found that lower distance between cytotoxic T cells, T helper cells and cancer cells was significantly associated with increased disease-free survival. An unsupervised trained model that clustered tumours based on the median distance between immune cells and cancer cells, as well as protein expression profiles, successfully classified patients into lowrisk and highrisk groups (Discovery cohort: p = 0.01, Validation cohort: p = 0.003).

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Predictive biomarkers of colon cancer immunotherapy: Present and future

Cited by 60 publications

References 191 publications

CDX-2 expression correlates with clinical outcomes in MSI-H metastatic colorectal cancer patients receiving immune checkpoint inhibitors

CDX-2 expression correlates with clinical outcomes in MSI-H metastatic colorectal cancer patients receiving immune checkpoint inhibitors

Rheumatic Immune-Related Adverse Events due to Immune Checkpoint Inhibitors—A 2023 Update

Spatial Effects of Infiltrating T cells on Neighbouring Cancer Cells and Prognosis in Stage III CRC patients

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