Mismatch repair-deficient colorectal cancer: a model of immunogenic and immune cell-rich tumor despite nonsignificant programmed cell death ligand-1 expression in tumor cells.

Mismatch repair-deficient (dMMR) colorectal cancers (CRCs) are good responders to anti-programmed cell death ligand-1 (PD-L1) immunotherapy, but the value of PD-L1 testing remains unclear. We studied PD-L1 expression and the tumor immune microenvironment in dMMR CRC as a model of good responders to immunotherapy. We examined 35 dMMR and 34 mismatch repair-proficient (pMMR) CRCs using immune cell markers (CD3, CD4, CD8, CD20, CD68, and FOXP3) as well as programmed cell death receptor-1 (PD-1) and PD-L1 immunohistochemistry staining in whole tumor specimens and tissue microarray slides to compare 4 PD-L1 immunohistochemistry clones (SP142, E1L3N, 22C3, and 28.8). We observed no significant difference in PD-L1 expression between dMMR and pMMR CRCs. Only 2 dMMR tumors had membranous PD-L1 staining. Expression of PD-L1 was greater in stromal immune cells of dMMR CRC, which also contained more numerous intraepithelial (CD3+, CD8+, FOXP3+, and PD-1+) and stromal (CD8+, PD-1+) lymphocytes than did pMMR tumors. Immune cell quantification discriminated better between dMMR and pMMR tumors than did PD-L1 expression. Tumor heterogeneity and variations in PD-L1 expression were noted with different antibodies, especially for PD-L1+ immune cells, which were more numerous at the invasion margin. Given the poor correlation with mismatch repair status and technical limitations, the value of PD-L1 testing to accompany the development of anti-PD-1/PD-L1 immunotherapy remains unclear. Further clinical trials are required to determine which parameters are valuable predictive biomarkers of the response to immunotherapy among mismatch repair status, PD-L1 expression, and immune cell quantification in CRC.

Le Flahec G ，Badic B ，Guibourg B ，Doucet L ，Bail JP ，Marcorelles P ，Schick U ，Uguen A ... -  《-》

High density of cytotoxic T-lymphocytes is linked to tumoral PD-L1 expression regardless of the mismatch repair status in colorectal cancer.

Möller K ，Blessin NC ，Höflmayer D ，Büscheck F ，Luebke AM ，Kluth M ，Hube-Magg C ，Zalewski K ，Hinsch A ，Neipp M ，Mofid H ，Lárusson H ，Daniels T ，Isbert C ，Coerper S ，Ditterich D ，Rupprecht H ，Goetz A ，Bernreuther C ，Sauter G ，Uhlig R ，Wilczak W ，Simon R ，Steurer S ，Minner S ，Burandt E ，Krech T ，Perez D ，Izbicki JR ，Clauditz TS ，Marx AH ... -  《-》

Intertumoral Heterogeneity of CD3(+) and CD8(+) T-Cell Densities in the Microenvironment of DNA Mismatch-Repair-Deficient Colon Cancers: Implications for Prognosis.

Colorectal cancers with deficient DNA mismatch repair (dMMR) are presumed to uniformly have dense lymphocytic infiltration that underlies their favorable prognosis and is critical to their responsiveness to immunotherapy, as compared with MMR-proficient (pMMR) tumors. We examined T-cell densities and their potential heterogeneity in a large cohort of dMMR tumors. CD3+ and CD8+ T-cell densities were quantified at the invasive margin (IM) and tumor core (CT) in 561 stage III colon cancers (dMMR, n = 278; pMMR, n = 283) from a phase III adjuvant trial (N0147). Their association with overall survival (OS) was determined using multivariable Cox analysis. Although CD3+ and CD8+ T-cell densities in the tumor microenvironment were higher in dMMR versus pMMR tumors overall, intertumoral heterogeneity in densities between tumors was significantly higher by 30% to 88% among dMMR versus pMMR cancers (P < 0.0001 for all four T-cell subtypes [CD3+IM, CD3+CT, CD8+IM, CD8+CT]). A substantial proportion of dMMR tumors (26% to 35% depending on the T-cell subtype) exhibited T-cell densities as low as that in the bottom half of pMMR tumors. All four T-cell subtypes were prognostic in dMMR with CD3+IM being the most strongly prognostic. Low (vs. high) CD3+IM was independently associated with poorer OS among dMMR (HR, 4.76; 95% confidence interval, 1.43-15.87; P = 0.0019) and pMMR tumors (P = 0.0103). Tumor-infiltrating T-cell densities exhibited greater intertumoral heterogeneity among dMMR than pMMR colon cancers, with CD3+IM providing robust stratification of both dMMR and pMMR tumors for prognosis. Potentially, lower T-cell densities among dMMR tumors may contribute to immunotherapy resistance.

Yoon HH ，Shi Q ，Heying EN ，Muranyi A ，Bredno J ，Ough F ，Djalilvand A ，Clements J ，Bowermaster R ，Liu WW ，Barnes M ，Alberts SR ，Shanmugam K ，Sinicrope FA ... -  《-》

Loss of survival advantage for deficient mismatch repair in patients with advanced colorectal cancer may be caused by changes in prognostic value of CD8+T cell.

Wang B ，Li F ，Guo L ，Lu S ，Ma J ，Ma Y ，Meng Y ，Wang J ，Zhou X ，Fu W ... -  《World Journal of Surgical Oncology》

PD-L1 protein expression in tumour cells and immune cells in mismatch repair protein-deficient and -proficient colorectal cancer: the foundation study using the SP142 antibody and whole section immunohistochemistry.

Routine application of PD-L1 immunohistochemistry (IHC) in colorectal cancer (CRC) is limited due to lack of standardized scoring criteria, antibody clones, and intratumoral staining heterogeneity. We assessed PD-L1 protein expression on full face CRC tissue sections and applied two algorithms based on the published clinical trials that support the recent FDA approval for immune checkpoint inhibitors (ICPI) therapy in non-small cell lung cancer (NSCLC). PD-L1/CD274 IHC (Roche/Ventana, clone SP142) was performed on representative tumour blocks from 52 mismatch repair-deficient (MMR-D) and 52 MMR-proficient (MMR-P) CRCs. Membranous PD-L1 expression was scored for the tumour cell (TC) and tumour-infiltrating immune cell (IC) components. PD-L1 positivity status was determined based on the published NSCLC clinical trials that utilized the Ventana SP142 assay. Hybrid capture-based comprehensive genomic profiling (CGP) was performed on a separate set of 2268 clinically advanced CRCs and the frequency of PD-L1/PD-L2 amplification was determined. PD-L1 expression in the TC and IC correlated with MMR-D (p=0.013, p<0.0001), T stage (p=0.036, p=0.0036) and clinical stage (p=0.022, p=0.0037). PD-L1 positivity status correlated with MMR-D by two algorithms. Five of 2268 (<1%) advansced CRCs demonstrated amplification of either the PD-L1 or PD-L2 genes by CGP. PD-L1 expression in TC and IC is associated with advanced stage and MMR-D. PD-L1 positivity status by the published algorithm is associated with MMR-D. PD-L1 amplification is extremely uncommon in CRC. Evaluation of whole tissue section and incorporation of IC staining enhance the sensitivity to screen patients who may benefit from ICPI therapy.

El Jabbour T ，Ross JS ，Sheehan CE ，Affolter KE ，Geiersbach KB ，Boguniewicz A ，Ainechi S ，Bronner MP ，Jones DM ，Lee H ... -  《-》