Abstract 15P
Background
The 4 main proteins of the mismatch repair (MMR) system form 2 heterodimers: MutLα (MLH1 and PMS2) and MutSα (MSH2 and MSH6). A loss of any of those proteins defines deficient MMR (dMMR) phenotype. However, the impact of dysfunctional heterodimer (i.e., loss of expression of MLH1 and/or PMS2 vs. MSH2 and/or MSH6) on intratumoral tumor infiltrating lymphocytes (iTIL), which are associated to prognosis, needs to be elucidated. We aim to analyze dMMR CRC features based on the altered heterodimer, focusing on iTIL.
Methods
Fifty-nine patients from 2 institutions operated for dMMR stage (S) II and III CRC between 2005-2021 have retrospectively been selected. Statistical comparisons have been performed between the groups according to SII vs SIII, iTIL vs no-iTIL, and MutLα vs MutSα, using Chi-square to assess its significance.
Results
The median age at diagnosis was 64 years. Main characteristics were: SII (54.3%), adenocarcinoma (mucinous < 50%) (74.6%) and indication of adjuvant treatment (57.6%). 12 (20.3%) out of 32 patients who do not meet sporadic dMMR criteria, have been diagnosed with Lynch syndrome in a Genetic Counselling Unit and 9 were not studied. The distribution of iTIL according to altered heterodimer and stage are shown in the table. In our cohort, iTIL were detected more frequently in SII tumors (56.8 vs 43.2% of SIII) whereas no-iTIL (N=15) were more common in SIII tumors (53.3 vs 46.7% of SII). iTIL were more frequently associated with MutLα alteration (76.5%) compared to MutSα alteration (71.4%). One SIII CRC patient had mixed alteration (MutSα & MutLα) and no-iTIL. No statistically differences were found. Table: 15P
iTIL distribution according to altered heterodimer and stage of the disease
| Stage II | Stage III | TOTAL | ||
| iTIL | MutLα only | 21 (84) | 18 (94.7) | 44 (74.6) |
| MutSα only | 4 (16) | 1 (5.3) | ||
| MutSα & MutLα | 0 (0) | 0 (0) | ||
| TOTAL | 25 (56.8) | 19 (43.2) | ||
| No iTIL | MutLα only | 7 (100) | 5 (62.5) | 15 (25.4) |
| MutSα only | 0 (0) | 2 (25) | ||
| MutSα & MutLα | 0 (0) | 1 (12.5) | ||
| TOTAL | 7 (46.7) | 8 (53.3) | ||
| Total | 32 (54.2) | 27 (45.8) | 59 |
Conclusions
In our cohort, iTIL are more frequent in lower-stage tumors and those with MutLα alterations. If different iTIL pattern among MutLα and MutSα alterations are confirmed, the MMR alteration pattern could have prognostic impact and predict response to immunotherapy.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.