scholarly journals Clinical Impact of Tumor-Infiltrating Lymphocytes and PD-L1-Positive Cells as Prognostic and Predictive Biomarkers in Urological Malignancies and Retroperitoneal Sarcoma

Cancers ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 3153
Author(s):  
Makito Miyake ◽  
Shunta Hori ◽  
Takuya Owari ◽  
Yuki Oda ◽  
Yoshihiro Tatsumi ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Retroperitoneal Sarcoma ◽  
Prognostic Impact ◽  
Lymphocyte Migration ◽  
Primary Tumors ◽  
Urological Malignancies ◽  
Infiltrating Lymphocytes ◽  
Shed Light

Over the past decade, an “immunotherapy tsunami”, more specifically that involving immune checkpoint inhibitors (ICIs), has overtaken the oncological field. The interaction and cross-talk among tumor cells and several immune cells in the tumor microenvironment are dynamic and complex processes. As immune contexture can vary widely across different types of primary tumors and tumor microenvironments, there is still a significant lack of clinically available definitive biomarkers to predict patient response to ICIs, especially in urogenital malignancies. An increasing body of evidence evaluating urological malignancies has proven that tumor-infiltrating lymphocytes (TILs) are a double-edged sword in cancer. There is an urgent need to shed light on the functional heterogeneity in the tumor-infiltrating immune system and to explore its prognostic impact following surgery and other treatments. Notably, we emphasized the difference in the immunological profile among urothelial carcinomas arising from different primary origins, the bladder, renal pelvis, and ureter. Significant differences in the density of FOXP3-positive TILs, CD204-positive tumor-infiltrating macrophages, PD-L1-positive cells, and colony-stimulating factors were observed. This review discusses two topics: (i) the prognostic impact of TILs and (ii) predictive biomarkers for ICIs, to shed light on lymphocyte migration in four solid tumors, the urothelial carcinoma, renal cell carcinoma, prostate cancer, and retroperitoneal sarcoma.

scholarly journals Tumor-Infiltrating Lymphocytes and Breast Cancer: Are Immune Checkpoint Inhibitors Ready for Prime Time in Breast Cancer?

2016 ◽  
Vol 33 (4) ◽  
pp. 237-246 ◽  
Author(s):  
Ana Cvetanović ◽  
Slađana Filipović ◽  
Nikola Živković ◽  
Miloš Kostić ◽  
Svetislav Vrbić ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Biology ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Breast Tumors ◽  
Prime Time ◽  
Infiltrating Lymphocytes

SummaryIn recent years, results obtained from different studies with large cohorts have revealed a bond between the presence of extensive lymphocytic infiltration and favourable prognostic associations in the early-stage of breast cancer (BC) and high response rates to neoadjuvant chemotherapy. Examiners used tumors from large cohorts of patients who took part in randomized neoadjuvant and adjuvant clinical trials. The importance of tumor infiltrating lymphocytes (TILs) appears to be subtype-specific and varies depending on the histological characteristics of the tumor. TILs have proven to be a good prognostic marker, but only in highly proliferative breast tumors such as triple negative breast tumors (TNBC) or HER 2 positive BC.In the era when standard, well-known, prognostic and predictive biomarkers are ever changing and the use of molecular profiling analyses are increasing, we are looking for techniques to improve our understanding of tumor biology and improve patient outcome. The relevance of TILs cannot be ignored but needs to be properly evaluated in larger prospective studies which must encompass the parameters set out in previous studies. The use of TILs as prognostic biomarkers in early breast cancer may represent a new dawn, and use of immunotherapy, especially immune checkpoint inhibitors, probably is the future for the breast cancer but it is not yet ready for prime time.

Effect of CTLA-4 overexpression on response to ipilimumab in melanoma.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 190-190
Author(s):  
Mary Nesline ◽  
Igor Puzanov ◽  
Marc S. Ernstoff ◽  
Sarabjot Pabla ◽  
Jeffrey M. Conroy ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Checkpoint Inhibitors ◽  
Therapy Group ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Immune Gene ◽  
Formalin Fixed Paraffin ◽  
Significant Difference ◽  
Formalin Fixed Paraffin Embedded ◽  
Infiltrating Lymphocytes

190 Background: CD8 positive tumor infiltrating lymphocytes (TILS) are highly associated with immune response and prognosis, and are also under investigation as a marker of response to checkpoint inhibitors. Given lack of predictive biomarkers for ipilimumab, growing number of trials for new indications for combination ipilimumab + nivolumab, and evidence to support therapeutic target overexpression as markers of response, we examined the role of CTLA-4 expression and TILS in response to ipilimumab and combination ipilimumab + nivolumab in melanoma. Methods: Formalin-fixed paraffin embedded melanoma samples taken prior to treatment by ipilimumab (n = 36) or combination ipilimumab + nivolumab (n = 10) were evaluated by a comprehensive immune gene expression profile to establish the relationship between CTLA-4 and CD8 and therapeutic response (RECIST v1.1). Results: Increased CTLA-4 expression was moderately associated with increased TILS (r2= .41, p = .004). This was observed in the monotherapy group (r2= .38, p = .02), and was higher in the smaller combination therapy group, though not statistically significant (r2= .59, p = .06). Higher levels of TILS were observed in responders who achieved clinical benefit from either regimen within 6 months (n = 20). No significant difference was observed between responders (M = 57.1, SD = 30.2) and nonresponders (M = 48.6, SD = 32.9); t(44) = -.895, p = .376. Lower levels of CTLA-4 were observed in responders who achieved clinical benefit from either regimen within 6 months. No significant difference was observed between responders (M = 54, SD = 35) and nonresponders (M = 38.7, SD = 26.8); t(44) = 1.70, p = .09. The ratio of TILS to CTLA-4 expression was higher in responders who achieved clinical benefit within 6 months (n = 20).No significant difference was observed between responders (M = 5.2, SD = 14.0) and nonresponders (M = 1.4, SD = 2.7); t(41) = -1.2, p = .212. Conclusions: While not statistically significant, CTLA-4 expression in melanoma patients treated with either ipilimumab or combination ipilimumab + nivolumab was lower in responders compared to nonresponders. This analysis does not support the concept that over-expression of CTLA-4 is a biomarker of response to anti-CTLA-4 therapy.

Tumor mutational load in gynecological and breast cancer.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 44-44 ◽  
Author(s):  
Filipa Lynce ◽  
Joanne Xiu ◽  
Elias Obeid ◽  
Antoinette R. Tan ◽  
Zoran Gatalica ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Therapeutic Response ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Molecular Profiling ◽  
Mutational Load ◽  
Wild Type ◽  
Test Standardization ◽  
Infiltrating Lymphocytes

44 Background: Lack of test standardization and conflicting results on PD1 and PD-L1 immunohistochemistry (IHC) assays challenge their use as predictive biomarkers for checkpoint inhibitors. High tumor mutational load (TML) has been linked to therapeutic response with immune checkpoint inhibition in melanoma, lung and colorectal cancer. Herein, we explore association of TML and PD1/PD-L1 expression in gynecological (GC) and breast cancer (BC). As secondary aim we explore the association of TML with BRCA1/2 mutations. Methods: De-identified data from molecular profiling on GC and BC tumors from the CARIS Life Sciences database was analyzed after obtaining IRB approval. TML was defined as the total number of nonsynonymous, somatic mutations per Mb sequenced with a 592-gene panel. PD-1 IHC was tested on Tumor Infiltrating Lymphocytes (TIL) with the cutoff of 1/HPF; PD-L1 expression was measured on tumor cells with the cutoff of 2+, 5%. Biomarker association was tested with ANOVA test (SPSS v23, IBM). Results: As shown in table, cervical (CC) and endometrial cancers (EC) had the highest TML and squamous CC and triple negative BC (TNBC) tumors with highest PD-L1. In EC, MSI-H was associated with higher TML when compared to MSS (20.1 vs. 6.1, p<0.001); 4 POLE-mutated tumors all carried TML (36-678) higher than mean (11.5). TML was not associated with PD1 or PDL1 positivity in any of the diseases. BRCA1/2 mutations were associated with higher mean TML in ovarian cancer (OC) (6.8 vs. 5.4 in wild type, p<0.001) but not in BC (6.3 vs. 6.8 in wild type, p=0.48). Conclusions: In this sample of patients who underwent molecular profiling, there was no association between TML and PD1 or PD-L1 expression. Association between BRCA1/2 tumor mutations and TML in OC is worth exploring. High TML in CC and EC support the development of immunotherapy for these diseases. [Table: see text]

scholarly journals POLE and Mismatch Repair Status, Checkpoint Proteins and Tumor-Infiltrating Lymphocytes in Combination, and Tumor Differentiation: Identify Endometrial Cancers for Immunotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Dandan Dong ◽  
Huajiang Lei ◽  
Duanya Liu ◽  
Hansong Bai ◽  
Yue Yang ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Patient Selection ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Tumor Grade ◽  
Prognostic Impact ◽  
High Grade ◽  
Checkpoint Proteins ◽  
Endometrial Cancers ◽  
Infiltrating Lymphocytes

ObjectiveAlthough Polymerase-epsilon (POLE)-mutated and mismatch repair (MMR)-deficient endometrial cancers (ECs) are considered as promising candidates for anti-PD-1/PD-L1 therapy, selecting only these patients may exclude other patients who could potentially respond to this treatment strategy, highlighting the need of additional biomarkers for better patient selection. This study aims to evaluate potential predictive biomarkers for anti-PD-1/PD-L1 therapy in addition to POLE mutation (POLEm) and MMR deficiency (MMRd).MethodsWe performed next generation sequencing for POLE from 202 ECs, and immunohistochemistry for MLH1, MSH2, MSH6, PMS2, CD3, CD8, PD-1 and PD-L1 on full-section slides from these ECs. We assessed the association of POLEm and MMRd with clinicopathologic features, expression of check point proteins, and density of tumor-infiltrating lymphocytes (TILs). Prognostic impact of these immune markers was also evaluated.ResultsPOLEm, MMRd and high-grade tumors exhibited elevated level of TILs. Increased expression of PD-1 and PD-L1 was observed in MMRd and high-grade ECs. A subgroup of MMR proficient ECs also harbored increased density of TILs, and positive expression of PD-1 and PD-L1. In addition, negative expression of checkpoint proteins and high density of TILs in combination was associated with good prognosis.ConclusionsCandidates for PD-1 blockade may extend beyond POLEm and MMRd ECs, additional factors such as tumor grade, and combination of TILs levels and expression of checkpoint proteins may need to be considered for better patient selection.

scholarly journals 353 Safety and efficacy of tumor infiltrating lymphocytes (TIL, LN-145) in combination with pembrolizumab for advanced, recurrent or metastatic HNSCC

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A378-A378
Author(s):  
Antonio Jimeno ◽  
Sophie Papa ◽  
Missak Haigentz ◽  
Juan Rodríguez-Moreno ◽  
Julian Schardt ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Checkpoint Inhibitors ◽  
Adoptive Cell Therapy ◽  
Single Agent ◽  
Objective Response ◽  
Tumor Resection ◽  
Tumor Infiltrating Lymphocytes ◽  
Open Label ◽  
Safety And Efficacy ◽  
Infiltrating Lymphocytes

BackgroundSingle agent checkpoint inhibitors (CPI) are an approved first or second-line therapy in head and neck squamous cell carcinoma (HNSCC), but their efficacy is limited. Adoptive cell therapy with tumor infiltrating lymphocytes (TIL, LN-145) has demonstrated efficacy in multiple malignancies alone or in combination with CPI. To improve HNSCC therapy, a combination of pembrolizumab and LN-145 was explored.MethodsIOV-COM-202 is an ongoing Phase 2 multicenter, multi-cohort, open-label study evaluating LN-145 in multiple settings and indications, and here we report cohort 2A which enrolled CPI naïve HNSCC patients who received the combination of LN-145 and pembrolizumab. Key eligibility criteria include up to 3 lines of prior therapy, ECOG <1, at least one resectable metastasis for LN-145 production, and at least another measurable lesion after tumor resection. Primary endpoints are ORR per RECIST v1.1 by investigator and safety as measured by the incidence of grade ≥ 3 treatment-emergent adverse events (TEAEs). LN-145 production method uses central GMP manufacturing in a 22-day process yielding a cryopreserved TIL product (figure 1). Preconditioning chemotherapy consists of cyclophosphamide/fludarabine, followed by LN-145, and then < 6 doses of IL-2 over <3 days. Pembrolizumab is initiated post-tumor harvest but prior to LN-145 and continues after LN-145 infusion Q3W until toxicity or progression (figure 2).ResultsNine (N=9) HNSCC patients have received LN-145 plus pembrolizumab, with a median duration of follow up of 6.9 months. Nine and 8 patients were evaluable for safety and efficacy, respectively. Mean number of prior therapies was 1.1 with 89% of the patients having received prior chemotherapy. Four were HPV+, 2 HPV-, 3 unknown. The Treatment Emergent Adverse Event (TEAE) profile was consistent with the underlying advanced disease and the known AE profiles of pembrolizumab, the lymphodepletion and IL-2 regimens. The most common TEAE were chills, hypotension, anemia, thrombocytopenia, pyrexia, fatigue and tachycardia. Four patients had a confirmed, objective response with an ORR of 44% (1 CR, 3 PR, 4 SD, 1 NE) per RECIST 1.1. The disease control rate at data cutoff was 89% in 9 patients, and 7 of the 8 evaluable patients (87.5%) had a reduction in target lesions. Median DOR was not reached.Abstract 353 Figure 1Iovance LN-145 (autologous TIL cell therapy product) ManufacturingAbstract 353 Figure 2IOV-COM-202 Study SchemaConclusionsLN-145 can be safely combined with pembrolizumab in patients with metastatic HNSCC. LN-145 plus pembrolizumab shows early signs of improved efficacy particularly when compared with literature reports of pembrolizumab alone in a comparable patient population. Enrollment is ongoing and updated data will be presented.Trial RegistrationNCT03645928Ethics ApprovalThe study was approved by Advarra Institutional Review Board, under protocol number: Pro00035064.

scholarly journals Expression of Immune Checkpoint Regulators IDO, VISTA, LAG3, and TIM3 in Resected Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2689
Author(s):  
Felix Popp ◽  
Ingracia Capino ◽  
Joana Bartels ◽  
Alexander Damanakis ◽  
Jiahui Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Checkpoint ◽  
Patient Survival ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Ductal Adenocarcinoma ◽  
Lymph Node Status ◽  
Clinicopathologic Parameters ◽  
Survival Differences ◽  
Infiltrating Lymphocytes

Pancreatic cancer features elaborate mechanisms of immune evasion. The potential of new immune molecules was explored to restore the antitumor immune response. If these immune molecules are associated with poor survival, specific drugs could take effect. Here, we analyze the expression of VISTA, LAG3, IDO, and TIM3 on tumor-infiltrating lymphocytes (TILs) and its impact on patient survival. We analyzed 153 pancreatic cancer patients from the prospectively managed database of the multicentered PANCALYZE study. Immunohistochemistry on a tissue microarray assessed VISTA, LAG3, IDO, and TIM3 expression of TILs from the patients undergoing primary resection. Complementarily, we analyzed publicly available transcriptomic data (n = 903). Successful completion of chemotherapy, and lymph node status were independent predictors of survival in the multivariate analysis of the clinicopathologic parameters. Fifteen tumors were exclusively VISTA-positive, thirteen tumors expressed VISTA together with TIM3, and ten tumors expressed VISTA together with IDO. Patients featuring tumors with high numbers of IDO-positive TILs had better patient survival (p = 0.037). VISTA, LAG3, and TIM3 expression did not correlate with survival. The analysis of publicly available data did not show survival differences. Tumors rarely co-express more than two immune molecules at the same time, and VISTA is most frequently co-expressed. Although IDO generally inhibits T-cell proliferation, a high expression of IDO was associated with improved survival. We expect immune checkpoint inhibitors against VISTA, LAG3, and TIM3 to be inefficient in a clinical application.

scholarly journals Emerging Trends for Radio-Immunotherapy in Rectal Cancer

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1374
Author(s):  
Claudia Corrò ◽  
Valérie Dutoit ◽  
Thibaud Koessler
Keyword(s):  
Rectal Cancer ◽  
Tumor Microenvironment ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Infiltration ◽  
Emerging Trends ◽  
Tumor Mutational Burden ◽  
Microsatellite Stability

Rectal cancer is a heterogeneous disease at the genetic and molecular levels, both aspects having major repercussions on the tumor immune contexture. Whilst microsatellite status and tumor mutational load have been associated with response to immunotherapy, presence of tumor-infiltrating lymphocytes is one of the most powerful prognostic and predictive biomarkers. Yet, the majority of rectal cancers are characterized by microsatellite stability, low tumor mutational burden and poor T cell infiltration. Consequently, these tumors do not respond to immunotherapy and treatment largely relies on radiotherapy alone or in combination with chemotherapy followed by radical surgery. Importantly, pre-clinical and clinical studies suggest that radiotherapy can induce a complete reprograming of the tumor microenvironment, potentially sensitizing it for immune checkpoint inhibition. Nonetheless, growing evidence suggest that this synergistic effect strongly depends on radiotherapy dosing, fractionation and timing. Despite ongoing work, information about the radiotherapy regimen required to yield optimal clinical outcome when combined to checkpoint blockade remains largely unavailable. In this review, we describe the molecular and immune heterogeneity of rectal cancer and outline its prognostic value. In addition, we discuss the effect of radiotherapy on the tumor microenvironment, focusing on the mechanisms and benefits of its combination with immune checkpoint inhibitors.

Ανοσοθεραπεία ενάντια στον καρκίνο του παγκρέατος

2020 ◽  
Author(s):  
Παύλος Παπακοτούλας
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Ciclopirox Olamine ◽  
Ifn Γ ◽  
Infiltrating Lymphocytes

Το πιο συχνό είδος καρκίνου του παγκρέατος είναι το αδενοκαρκίνωμα του παγκρέατος. Το παγκρεατικό αδενοκαρκίνωμα είναι η 4η κύρια αιτία των θανάτων από καρκίνο παγκοσμίως. Περίπου 60-80% των ασθενών έχουν τη στιγμή της διάγνωσης προχωρημένη νόσο, επειδή ο καρκίνος εισβάλλει στους περιβάλλοντες ιστούς έξω από το πάγκρεας (τοπικά προχωρημένος), ή έχει δώσει μεταστάσεις έξω από το πάγκρεας (μεταστατικός). Καθώς η νόσος παρουσιάζει πολύ υψηλό ποσοστό θνητότητας, κρίνεται επιτακτική η ανάγκη ανεύρεσης νέων αποτελεσματικότερων θεραπειών. Με τη ανάπτυξη της μοριακής και βιολογικής κατανόησης της ογκογενετικής εξέλιξης, εφαρμόστηκαν νέες στρατηγικές στην αντιμετώπιση του καρκίνου και κατ’ επέκταση σε αυτόν της ανοσοθεραπείας του καρκίνου. Η κατανόηση των μοριακών μηχανισμών που διέπουν την ανοσοδιαφυγή των όγκων, αλλά και την αλληλεπίδραση των καρκινικών κυττάρων με τα κύτταρα του ανοσοποιητικού συστήματος, έχει δώσει τεράστια ώθηση στην ανοσοθεραπεία του καρκίνου την τελευταία δεκαετία. Τα κύτταρα του ανθρώπινου οργανισμού βρίσκονται υπό διαρκή ανοσιακή επιτήρηση και το ανοσοποιητικό σύστημα αποτελεί αποτρεπτικό μηχανισμό στον νεοπλασματικό μετασχηματισμό και τη δημιουργία νεοπλασιών. Κλινικό σημείο που επιβεβαιώνει τη θεωρία της ανοσοεπιτήρησης είναι η διαπίστωση της παρουσίας CD8+ T-λεμφοκυττάρων μέσα στους όγκους (Tumor Infiltrating Lymphocytes – TILs). Συνέπεια αυτού είναι και οι θεραπείες που βασίζονται στην καταστολή των σημείων ελέγχου του ανοσοποιητικού συστήματος (Immune Checkpoint Inhibitors). Είναι γνωστό ότι φάρμακα με αντιμυκητιακές ιδιότητες συμβάλλουν στην ενίσχυση του ανοσοποιητικού συστήματος. Ένα χαρακτηριστικό παράδειγμα είναι η κυκλοπιροξολαμίνη (Ciclopirox Olamine, CPX), που χορηγείται σε άτομα που ταλαιπωρούνται από μυκητιάσεις. Σύμφωνα με την παρούσα διατριβή η συγκεκριμένη θεραπεία μπορεί να μειώσει δραστικά την ταχύτητα εξέλιξης των καρκινικών όγκων, αλλά παράλληλα ενισχύει τη δράση των κυτταροστατικών που χορηγούνται στον ασθενή. Επίσης, η τινζαπαρίνη (Ηπαρίνη Χαμηλού Μοριακού Βάρους) χρησιμοποιείται για την πρόληψη και την αντιμετώπιση της φλεβικής θρομβοεμβολής, αλλά από τα αποτελέσματα της παρούσης διατριβής φαίνεται ότι μπορεί να διαδραματίζει ρόλο στην αντιμετώπιση του όγκου. Οι μηχανισμοί στους οποίους οφείλονται τα σημαντικά in vivο αποτελέσματα, είναι η αύξηση της IFN-γ, η αύξηση των CD8+ κυττάρων, η μείωση των Tregs κυττάρων, η μείωση της έκφρασης του VEGFR-2 και η αύξηση της απόπτωσης στα καρκινικά κύτταρα. Στην παρούσα διατριβή, προτείνεται πως η συνδυαστική θεραπεία με τη συμμετοχή της ανοσοθεραπείας, έχει προφανώς υψηλότερη αντινεοπλασματική επίδραση στη μείωση της ανάπτυξης του όγκου, υποδηλώνοντας μια συνεργική δράση. Αυτή η συνεργική στρατηγική μπορεί να ανοίξει νέους δρόμους για τη θεραπεία ασθενών με καρκίνο του παγκρέατος.

Association of KMT2C/D loss-of-function mutations with tumor infiltrating lymphocytes and response to immune checkpoint inhibitors in solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2587-2587
Author(s):  
Ruiqi Liu ◽  
Yanling Niu ◽  
Xin Zhang ◽  
Tonghui Ma
Keyword(s):  
Gene Expression ◽  
Colorectal Cancer ◽  
T Cells ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Loss Of Function ◽  
Cancer Types ◽  
Immune Related Genes ◽  
Infiltrating Lymphocytes

2587 Background: Dysregulation of HMTs plays an important role in tumorigenesis. KMT2C and KMT2D are enzymatically active scaffold proteins that form the core of mammalian COMPASS complexes, which methylate the histone 3 lysine 4. Both KMT2C and KMT2D are involved in the regulation of gene expression. Therefore, we explored the associations of KMT2C/D loss-of-function (LOF) mutations with the expression of immune-related genes, the levels of tumor infiltrating lymphocytes (TILs), and response to immune checkpoint inhibitors (ICIs). Methods: KMT2C/D LOF mutations were defined as nonsense, frameshift, splice site variants within consensus regions, start lost, and stop lost/gained variants. An ICIs treatment cohort from the MSKCC was used for exploring the associations between KMT2C/D LOF mutations and ICIs efficacy. The RNA-Seq data obtained from the TCGA cohort was used for analysis of gene expression and the levels of TILs using CIBERSORT. Results: In MSKCC pan-cancer dataset, patients with KMT2C/D LOF mutations had a relatively longer median overall survival (OS) compared to those with non-LOF mutations, although the result did not reach statistical significance (P = 0.0832). Then we analyzed the predictive roles of KMT2C/D LOF mutations for each cancer type. The results showed that the predictive role of KMT2C/D LOF mutations for the clinical efficacy of ICIs therapy was only observed in colorectal cancer (P = 0.045). However, we did not find the associations of KMT2C/D LOF mutations with ICIs efficacy in bladder cancer, breast cancer, melanoma, glioma, head and neck cancer, renal cell carcinoma, NSCLC, and esophagogastric cancer. Consistently, analysis of TILs in colorectal cancer revealed that KMT2C/D LOF was associated with increased infiltration of several types of immune cells, such as CD8+ T cells (P = 0.0001), activated NK cells (P = 0.0001), M1 macrophage (P = 0.0005), M2 macrophage (P = 0.0115), and neutrophils (P = 0.0209). Meanwhile, regulatory T cells (Tregs) (P = 0.0048) and M0 macrophage (P = 0.0043) were dramatically decreased in KMT2C/D LOF group for colorectal cancer. Moreover, there were no significant relationships between KMT2C/D LOF and the levels of TILs in other cancer types. Our data also demonstrated that KMT2C and KMT2D could regulate the expression of more than 30 immune-related genes in colorectal cancer. Conclusions: Our data indicated that KMT2C/D LOF mutations were significantly correlated with better outcomes of ICIs therapy in colorectal cancer, suggesting it can be as a useful predictor for response to ICIs in colorectal cancer. Meanwhile, we found the associations of KMT2C/D LOF with the levels of TILs in colorectal cancer, but not in other cancer types, indicating that the efficacy of ICIs was consistent with the levels of TILs.

Prognostic impact of tumor-infiltrating lymphocytes in non-small cell lung carcinomas

2021 ◽  
pp. 021849232110421
Author(s):  
Mona Mlika ◽  
Ayoub Saidi ◽  
Nesrine Mejri ◽  
Mehdi Abdennadher ◽  
Chokri Haddouchi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tumor Infiltrating Lymphocytes ◽  
Small Cell ◽  
Prognostic Impact ◽  
Small Cell Lung ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Lung Carcinomas ◽  
Forkhead Box ◽  
Infiltrating Lymphocytes

Introduction Tumor-infiltrating lymphocytes represent a pivotal component of the host anti-tumor response. Thus, they considerably influence the evolution of cancers including non-small cell lung carcinomas. Even if, this important role is consensual, many discordant results are published in the literature about the prognostic role of the different populations of tumor-infiltrating lymphocytes. The aim of our work was to evaluate the prognostic impact of CD8+, CD4+, and forkhead box protein P3+ lymphocytes in the tumor microenvironment of non-small cell lung carcinomas. Methods We conducted a retrospective descriptive study, which included non-small cell lung carcinomas diagnosed in the department of pathology and followed in the medical oncology department of the same hospital between 2011 and 2015. Tumor-infiltrating lymphocytes were analyzed by the immunohistochemical method for forkhead box protein P3, CD4, and CD8. Intratumoral and stromal-labeled lymphocytes were quantified by manual counting at high magnification (×400). Forkhead box protein P3+/CD8+, forkhead box protein P3+/CD4+, and CD8+/CD4+ ratios were subsequently calculated. The prognostic value of tumor-infiltrating lymphocytes was assessed in respect of overall survival, recurrence-free survival, and relapse-free survival. Results Thirty-nine patients were included. The mean age of patients was 59.6 years. A complete surgical resection ( p = 0.009), and a CD8/CD4 ratio ( p = 0.008) were prognostic factors for overall survival. Complete surgical resection ( p = 0.003), the forkhead box protein P3/CD8 ( p = 0.005), and forkhead box protein P3/CD4 ( p = 0.037) ratios were prognostic factors for recurrence-free survival. The CD8+ tumor-infiltrating lymphocytes rate ( p = 0.037) was a prognostic factor for relapse-free survival with a threshold of 67.8/high power field. Microscopic subtype ( p = 0.037) was a prognostic factor for relapse-free survival when only adenocarcinoma and squamous cell carcinoma were considered. In multivariate analysis, age ( p = 0.004) and a CD8/CD4 ratio ( p = 0.016) were independent predictors of overall survival. Conclusion Despite the limitations of our study, our results confirm the prognostic value of tumor-infiltrating lymphocytes in non-small cell lung carcinomas and the importance of the combined quantification of their different subpopulations.

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