Microsatellite instability (MSI-H) is associated with a high immunoscore but not with PD-L1 expression or increased survival in patients (pts.) with metastatic colorectal cancer (mCRC) treated with oxaliplatin (ox) and fluoropyrimidine (FP) with and without bevacizumab (bev): a pooled analysis of the AIO KRK 0207 and RO91 trials

Noepel-Duennebacke, Stefanie; Juette, Hendrik; Schulmann, Karsten; Graeven, U.; Porschen, Rainer; Stoehlmacher, Jan; Hegewisch‐Becker, Susanna; Raulf, Arne Peter; Arnold, Dirk; Reinacher‐Schick, Anke; Tannapfel, A.

doi:10.1007/s00432-021-03559-w

Cited by 8 publications

(7 citation statements)

References 22 publications

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“…Therefore, ICIs have exerted effective responses among dMMR CRCs because of the high immunogenicity in the tumor microenvironment ( 3 , 18 ). A large-scale case study previously reported microsatellite instability (MSI)-high (MSI-H) and immunoscore-low cases in 2.7% (15/550) of all CRC cases tested ( 19 ), suggesting that a fraction of the patients with MSI-H CRC showing low immune reaction might show relatively low TMB levels. MMR dysfunction results from a loss of function in any of the MMR genes encoding the four MMR proteins, MLH1, MSH2, MSH6 and PMS2 .…”

Section: Discussionmentioning

confidence: 99%

“…CRCs with MSS have a low mutation load in tumor cells (29,30) and a low number of presenting antigens, leading to a lower level of T-cell infiltration in the tumor microenvironment (4). However, previous studies have reported that 21-50% of CRCs with MSS actually showed high T-cell infiltration (19,31,32). In addition, pMMR CRCs with a high number of TILs showed therapeutic response to ICIs (30,33), suggesting that pMMR CRCs harbor antitumor immunogenic potential and may be therapeutically responsive to ICIs.…”

Section: Mmr-proficient Mmr-deficientmentioning

confidence: 99%

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Mismatch repair proteins expression and tumor‑infiltrating T‑cells in colorectal cancer

et al. 2022

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Microsatellite instability (MSI) and tumor mutational burden (TMB) are indicators of the tumor mutational load, which can lead to immune cell recruitment. By contrast, the number of tumor-infiltrating T cells (TITs) is indicative of the host immune response to tumor cells. The present study evaluated if the expression of mismatch repair (MMR) proteins can be used as a precise tool to assess immunogenicity in the tumor microenvironment. A total of 73 colorectal cancer cases were enrolled in the present study. MMR protein expression was assessed using four-antibodies immunohistochemistry (IHC) targeting MLH1, MSH2, MSH6 and PMS2. TIT was assessed through IHC by counting CD3 + and CD8 + cells in tumor. The enrolled cases were classified into four groups according to MMR and TIT status i) Mismatch repair-proficient (pMMR) and a high number of TITs (pMMR/TIT-H); ii) pMMR and a low number of TITs (pMMR/TIT-L); iii) mismatch repair-deficient (dMMR) and TIT-H (dMMR/TIT-H); and iv) dMMR/TIT-L]. The present study evaluated the clinicopathological characteristics of the four groups, in addition to the difference of TMB. TMB analysis was counted the number of the somatic mutations through multi-genes panel using next-generation sequencing. Clinicopathological characteristics, including age, sex, pathological depth of invasion and lymph node metastasis, were not found to be statistically different between dMMR/TIT-H and dMMR/TIT-L groups. Tumors among pMMR/TIT-H group were associated with poorly differentiation compared with those in pMMR/TIT-L group (P=0.025). The median TMB among the dMMR/TIT-H group was the highest in four groups but the median TMB was <10 muts/Mb in dMMR/TIT-L, pMMR/TIT-H and pMMR/TIT-L groups, respectively. However, one tumor in the pMMR/TIT-H group showed high TMB. The present findings suggest that assessing MMR status alone may not be sufficient to precisely evaluate the antitumor immune response in the tumor microenvironment.

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Section: Discussionmentioning

confidence: 99%

Section: Mmr-proficient Mmr-deficientmentioning

confidence: 99%

Mismatch repair proteins expression and tumor‑infiltrating T‑cells in colorectal cancer

et al. 2022

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“… 96 , 98 , 99 In mCRC patients, MSI‐H was confirmed to be associated with a high Immunoscore. 100 The expression of PD‐1/PD‐L1 was also significantly higher in I3 and I4 tumor patients in CRC, who might potentially benefit from ICI treatment. 98 , 101 In summary, researchers suggested that Immunoscore is a novel marker independent of microsatellites.…”

Section: Tumor Immune Microenvironment (Time) and Tumor‐infiltrating Lymphocytes (Tils)mentioning

confidence: 95%

“…Studies have found that in stage I‐III CRCs, the higher the density of immune cell infiltration, the higher was the patient score, and the better was the prognosis 96,98,99 . In mCRC patients, MSI‐H was confirmed to be associated with a high Immunoscore 100 . The expression of PD‐1/PD‐L1 was also significantly higher in I3 and I4 tumor patients in CRC, who might potentially benefit from ICI treatment 98,101 .…”

Section: Tumor Immune Microenvironment (Time) and Tumor‐infiltrating Lymphocytes (Tils)mentioning

confidence: 99%

Predictive molecular markers for the treatment with immune checkpoint inhibitors in colorectal cancer

Liu

2021

Clinical Laboratory Analysis

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Colorectal cancer is one of the most common malignant tumors and, hence, has become one of the most important public health issues in the world. Treatment with immune checkpoint inhibitors (ICIs) successfully improves the survival rate of patients with melanoma, non‐small‐cell lung cancer, and other malignancies, and its application in metastatic colorectal cancer is being actively explored. However, a few patients develop drug resistance. Predictive molecular markers are important tools to precisely screen patient groups that can benefit from treatment with ICIs. The current article focused on certain important predictive molecular markers for ICI treatment in colorectal cancer, including not only some of the mature molecular markers, such as deficient mismatch repair (d‐MMR), microsatellite instability‐high (MSI‐H), tumor mutational burden (TMB), programmed death‐ligand‐1 (PD‐L1), tumor immune microenvironment (TiME), and tumor‐infiltrating lymphocytes (TILs), but also some of the novel molecular markers, such as DNA polymerase epsilon (POLE), polymerase delta 1 (POLD1), circulating tumor DNA (ctDNA), and consensus molecular subtypes (CMS). We have reviewed these markers in‐depth and presented the results from certain important studies, which suggest their applicability in CRC and indicate their advantages and disadvantages. We hope this article is helpful for clinicians and researchers to systematically understand these markers and can guide the treatment of colorectal cancer.

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“…The immuno-score has been suggested to be superior to the conventional TNM classification in CRC, given its ability to differentiate patients with a better or worse prognosis in MSS and MSI disease, as across the various stages according to AJCC/UICC [68]. The measure of CD8+ cells and CD45RO+ memory cells in specific tumor regions (i.e., at the invasive front) has been, in fact, linked to longer overall survival in MSI-CRC patients [69]. This parameter is likely to be included in the TNM staging, similarly to its use for MSI, although some refinement is necessary in order to better define its reliability in stage III disease [36,44].…”

Section: Adaptive Immune Response and The Relevance Of Immune Parametersmentioning

confidence: 99%

Defects in MMR Genes as a Seminal Example of Personalized Medicine: From Diagnosis to Therapy

Buono

Gaiani

Poliani

et al. 2021

JPM

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Microsatellite instability (MSI) is the landmark feature of DNA mismatch repair deficiency, which can be found in 15–20% of all colorectal cancers (CRC). This specific set of tumors has been initially perceived as a niche for geneticists or gastroenterologists focused on inherited predispositions. However, over the years, MSI has established itself as a key biomarker for the diagnosis, then extending to forecasting the disease behavior and prognostication, including the prediction of responsiveness to immunotherapy and eventually to kinase inhibitors, and possibly even to specific biological drugs. Thanks to the contribution of the characterization of MSI tumors, researchers have first acknowledged that a strong lymphocytic reaction is associated with a good prognosis. This understanding supported the prognostic implications in terms of the low metastatic potential of MSI-CRC and has led to modifications in the indications for adjuvant treatment. Furthermore, with the emergence of immunotherapy, this strong biomarker of responsiveness has exemplified the capability of re-activating an effective immune control by removing the brakes of immune evasion. Lately, a subset of MSI-CRC emerged as the ideal target for kinase inhibitors. This therapeutic scenario implies a paradox in which appropriate treatments for advanced disease are effective in a set of tumors that seldom evolve towards metastases.

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Cited by 8 publications

References 22 publications

Mismatch repair proteins expression and tumor‑infiltrating T‑cells in colorectal cancer

Mismatch repair proteins expression and tumor‑infiltrating T‑cells in colorectal cancer

Predictive molecular markers for the treatment with immune checkpoint inhibitors in colorectal cancer

Defects in MMR Genes as a Seminal Example of Personalized Medicine: From Diagnosis to Therapy

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