Tumour infiltrating lymphocyte status is superior to histological grade, DNA mismatch repair and BRAF mutation for prognosis of colorectal adenocarcinomas with mucinous differentiation

Williams, David S.; Mouradov, Dmitri; Newman, Marsali; Amini, Elham; Nickless, David; Fang, Catherine; Palmieri, Michelle; Sakthianandeswaren, Anuratha; Li, Shan; Ward, Robyn L.; Hawkins, Nicholas J.; Skinner, Iain; Jones, Ian T.; Gibbs, Peter; Sieber, Oliver M.

doi:10.1038/s41379-020-0496-1

Cited by 21 publications

(26 citation statements)

References 49 publications

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“…Lymphocytic in ltration is a major immunological defense against tumor cells in solid tumors and is a potential predictor of CRC [26,27]. Williams et al 8 found TIL status to be a strong independent predictor of PFS in mucinous component tumors, and a superior predictor of prognosis compared with histological grade. The more TIL in ltrates in the tumor microenvironment, the better the prognosis may be.…”

Section: Discussionmentioning

confidence: 99%

“…Depending on the proportion of extracellular mucin, tumors were separated into three categories: 1) low mucin, extracellular mucin occupying < 50 % of the tumour; 2) moderate mucin, 50-80 % of the tumour; 3) high mucin, ≥ 80 % of the tumour. In terms of the microscopic morphology of tumour cells in mucin pools, three types were de ned: 1) strip predominant type, characterised by attened single-cell layers or strips of tumour cells located along the edge of mucin pools; 2) cluster predominant type, denoted by oating tumour cells forming clusters, acini, or cribriform sheets; 3) predominant signet ring cell type, in which signet ring cells compose ≥ 50 % of tumour cells [8]. The number of poorly differentiated clusters (PDCs) in a single eld of highest activity was graded as G1 (< 5 clusters), G2 (5 to 9 clusters), or G3 (≥ 10 clusters) under an objective lens with a magni cation of ×20 according to previous article [11].…”

Section: Histopathologic Evaluationsmentioning

confidence: 99%

“…TIL were scored blindly and independently by two observers (Xiaoli Jia and Bin Li). Density of TIL for these tumors as scored using H&E stained tissue sections has been reported previously [8,12]. Tumors were classi ed into TIL-low (< 2 TILs per hpf) and TIL-high (≥ 2 TILs per hpf) cases.…”

Section: Evaluation Of Tilmentioning

confidence: 99%

“…Till present, the prognostic value of MAC remains undetermined when the locations of the tumor, molecular alterations, population characteristics or different treatment plans are taken into account. Moreover, the prognostic signi cance of ≤ 50% tumour [8]. Gonzalez et al performed a stage-matched analysis and showed that Stagematched MAC and adenocarcinoma have similar outcomes, with no prognostic signi cance to mucinous histological subtype [5].…”

Section: Introductionmentioning

confidence: 99%

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Clinicopathological characteristics, molecular alterations and prognosis of mucinous histology in colorectal adenocarcinoma patients

Jia

Yan

2020

Preprint

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Background Mucinous adenocarcinoma (MAC) is conventionally diagnosed by WHO definition when the extracellular mucin is more than 50% of the tumour area. The study is aimed at analyzing the clinicopathological characteristics, mutation spectrum, and prognosis of the colorectal adenocarcinoma (CRC) with any mucinous proportion or feature. Methods Clinical and pathological information for 50 patients were reviewed and recorded. Mutation analyses for exon 2–4 of KRAS gene and exon 15 of BRAF gene were performed by Sanger sequencing. Expression of DNA mismatch repairs (MMRs) and P53 proteins was evaluated by immunohistochemistry (IHC). Density of tumour infiltrating lymphocyte (TIL) status was scored. We also evaluated the percentage of glands producing mucin and the morphology of the different tumor cells types in mucin pools. We retrospectively analyzed prognosis of 43 patients with Stage II-III MAC. The primary outcome was progression-free survival (PFS). Results The overall frequencies of KRAS and BRAF mutations were 37.9% and 4.4%, respectively. Patients with MAC exhibiting high levels of mucin were related to the increase of tumor diameter (P = 0.038), but were not associated with any of the other clinicopathological parameters. The proportion or variable morphology of mucinous component did not stratify PFS in Stage II-III tumours. It is interesting to note that male patients had lower TIL compared with female patients (P = 0.018). TIL-low tumors were also correlated with advanced stage (P = 0.041). TIL status was a strong independent predictor of PFS in stage II-III mucinous component tumours (p < 0.001). All four IV stage patients were also classified into TIL-low case. No parameters were independently associated with outcome after adjusting for tumour stage in multivariate analysis. Conclusions TIL status could more accurately determine the biology of the MAC feature for appropriate management, irrespective of quantity or morphology of mucinous component.

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Section: Discussionmentioning

confidence: 99%

Section: Histopathologic Evaluationsmentioning

confidence: 99%

Section: Evaluation Of Tilmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Clinicopathological characteristics, molecular alterations and prognosis of mucinous histology in colorectal adenocarcinoma patients

Jia

Yan

2020

Preprint

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“…In TIL cells from different tumor sources, the proportion of CD4 + T cells and CD8 + T cells is different, mainly CD8 + T cells in most cases, which can specifically recognize and kill tumors, and their number and activity determine the effect of antitumor immunity, and also affect the efficacy of ICB. Some studies believe that TIL status is a better predictor of tumor prognosis than histological grade, DNA MMR (Mismatch repair) and BRAF mutations 34 . The decrease in intratumoral CD8 + TIL density was significantly correlated with the deterioration of RFS (Recurrence Free Survival) 35 .…”

Section: Influence Of Tumor Microenvironment On Clinical Treatment Rementioning

confidence: 99%

Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker

Wang

2020

Cancer Medicine

116

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Immunocheckpoint proteins of tumor infiltrating lymphocytes play an important role in tumor prognosis in the course of tumor clinicopathology. PD‐1 (Programmed cell death protein 1) is an important immunosuppressive molecule. By binding to PD‐L1 (programmed cell death‐ligand 1), it blocks TCR and its costimulus signal transduction, inhibits the activation and proliferation of T cells, depletes the function of effector T cells, and enables tumor cells to achieve immune escape. In recent years, immunocheckpoint blocking therapy targeting the PD‐1/PD‐L1 axis has achieved good results in a variety of malignant tumors, pushing tumor immunotherapy to a new milestone, such as anti‐PD‐1 monoclonal antibody Nivolumab, Pembrolizumab, and anti‐PD‐L1 monoclonal antibody Atezolizumab, which are considered as potential antitumor drugs. It was found in clinical use that some patients obtained long‐term efficacy, but most of them developed drug resistance recurrence in the later stage. The high incidence of drug resistance (including primary and acquired drug resistance) still cannot be ignored, which limited its clinical application and became a new problem in this field. Due to tumor heterogeneity, current limited research shows that PD‐1 or PD‐L1 monoclonal antibody drug resistance may be related to the following factors: mutation of tumor antigen and antigen presentation process, multiple immune checkpoint interactions, immune microenvironment changes dynamically, activation of oncogenic pathways, gene mutation and epigenetic changes of key proteins in tumors, tumor competitive metabolism, and accumulation of metabolites, etc, mechanisms of resistance are complex. Therefore, it is the most urgent task to further elucidate the mechanism of immune checkpoint inhibitor resistance, discover multitumor universal biomarkers, and develop new target agents to improve the response rate of immunotherapy in patients. In this study, the mechanism of anti‐PD‐1/PD‐L1 drug resistance in tumors, the potential biomarkers for predicting PD‐1 acquired resistance, and the recent development of combination therapy were reviewed one by one. It is believed that, based on the complex mechanism of drug resistance, it is of no clinical significance to simply search for and regulate drug resistance targets, and it may even produce drug resistance again soon. It is speculated that according to the possible tumor characteristics, three types of treatment methods should be combined to change the tumor microenvironment ecology and eliminate various heterogeneous tumor subsets, so as to reduce tumor drug resistance and improve long‐term clinical efficacy.

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CMTM6 expression in M2 macrophages is a potential predictor of PD-1/PD-L1 inhibitor response in colorectal cancer

Lan

et al. 2021

Cancer Immunol Immunother

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Background CMTM6 is a novel key regulator of PD-L1. High expression of both CMTM6 and PD-L1 may predict the benefit of PD-1 axis blockade in lung cancer. We aimed to investigate the expression pattern of CMTM6 between mismatch repair-defective (dMMR) and mismatch repair-proficient (pMMR) colorectal cancer (CRC) tissues and assess its correlation with the response to PD-1/PD-L1 pathway blockade. Methods Immunohistochemistry (IHC) was used to analyze CMTM6 and PD-L1 expression and immune cell density in dMMR/pMMR CRC. Quantitative multiplex immunofluorescence (IF) was performed to detect CMTM6, PD-L1, CD4, CD8, CD68 and CD163 expression in CRC patients treated with PD-1/PD-L1 inhibitors. Result IHC analysis showed that CMTM6 and PD-L1 were both expressed in tumor cells (TCs) and invasion front immune cells (ICs). CMTM6 and PD-L1 expression and CD4+, CD8+, CD68+ or CD163+ cell density were significantly higher in dMMR CRC patients than in pMMR CRC patients. CMTM6 expression was positively correlated with PD-L1 expression and CD163+ M2 macrophage density in dMMR CRC. IF analysis showed that the coexpression rate of CMTM6/PD-L1 and the expression rate of CMTM6 in CD8+ T cells and CD163+ M2 macrophages were significantly increased in the group that exhibited clinical benefit. CMTM6 expression in M2 macrophages was identified as the best biomarker for predicting the responsiveness to PD-1/PD-L1 inhibitors. Conclusions CMTM6 expression in M2 macrophages may predict the PD-1/PD-L1 inhibitor response rate in CRC patients more accurately than dMMR/microsatellite instability-high (MSI-H) status. It can also identify pMMR CRC patients who could benefit from PD-1/PD-L1 inhibitors.

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Tumour infiltrating lymphocyte status is superior to histological grade, DNA mismatch repair and BRAF mutation for prognosis of colorectal adenocarcinomas with mucinous differentiation

Cited by 21 publications

References 49 publications

Clinicopathological characteristics, molecular alterations and prognosis of mucinous histology in colorectal adenocarcinoma patients

Clinicopathological characteristics, molecular alterations and prognosis of mucinous histology in colorectal adenocarcinoma patients

Study and analysis of antitumor resistance mechanism of PD1/PD‐L1 immune checkpoint blocker

CMTM6 expression in M2 macrophages is a potential predictor of PD-1/PD-L1 inhibitor response in colorectal cancer

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