Immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has shown limited efficacy in treating ovarian cancer (OC), possibly due to diverse T cell infiltration patterns in the tumor microenvironment. This review explores how neoadjuvant chemotherapy (NACT) impacts the immune landscape of OC, focusing on tumor-infiltrating lymphocytes (TILs), PD-1/PD-L1 expression, and their clinical implications. A comprehensive literature search across four databases yielded nine relevant studies. These studies evaluated stromal (sTILs) and intra-epithelial (ieTILs) TILs before and after NACT. sTIL responses varied, impacting prognostic outcomes, and ieTILs increased in some patients without clear survival associations. PD-L1 expression after NACT correlated with improved overall survival (OS), and increases in granzyme B+ and PD-1 correlated with longer progression-free survival (PFS). Remarkably, reduced FoxP3+ TILs post-NACT correlated with better prognosis. NACT often increases sTIL/ieTIL and CD8+ subpopulations, but their correlation with improved PFS and OS varies. Upregulation of co-inhibitory molecules, notably PD-L1, suggests an immunosuppressive response to chemotherapy. Ongoing trials exploring neoadjuvant ICIs and chemotherapy offer promise for advancing OC treatment. Standardized measurements assessing TIL density, location, and heterogeneity are crucial for addressing genetic complexity and immunological heterogeneity in OC.

BACKGROUND: Microsatellite instability (MSI) status and tumour-infiltrating lymphocytes (TIL) are established prognostic factors in colorectal cancer. Previous studies evaluating the combination of TIL and MSI status identified distinct colorectal cancer subtypes with unique prognostic associations. However, these studies were often limited by sample size, particularly for MSI-high (MSI-H) tumours, and there is no comprehensive summary of the available evidence. We aimed to review the literature to compare the survival outcomes associated with the subtypes derived from the integrated MSI-TIL classification in patients with colorectal cancer.
METHODS: In this systematic review and network meta-analysis, we searched PubMed, Embase, Scopus, and the Cochrane Library without language restrictions, for articles published between Jan 1, 1990, and March 13, 2024. Patient cohorts comparing different combinations of TIL (high or low) and MSI status (MSI or microsatellite stable [MSS]) in patients with surgically resected colorectal cancer were included. Studies were excluded if they focused on neoadjuvant therapy or on other immune markers such as B cells or macrophages. Methodological quality assessment was done with the Newcastle-Ottawa scale; data appraisal and extraction was done independently by two reviewers. Summary estimates were extracted from published reports. The primary outcomes were overall survival, disease-free survival, and cancer-specific survival. A frequentist network meta-analysis was done to compare hazard ratios (HRs) and 95% CI for each outcome. The MSI-TIL subgroups were prognostically ranked based on P-score, bias, magnitude, and precision of associations with each outcome. The protocol is registered with PROSPERO (CRD42023461108).
RESULTS: Of 302 studies initially identified, 21 studies (comprising 14 028 patients) were included in the systematic review and 19 (13 029 patients) in the meta-analysis. Nine studies were identified with a low risk of bias and the remaining ten had a moderate risk of bias. The MSI-TIL-high (MSI-TIL-H) subtype exhibited longer overall survival (HR 0·45, 95% CI 0·34-0·61; I2=77·7%), disease-free survival (0·43, 0·32-0·58; I2=61·6%), and cancer-specific survival (0·53, 0·43-0·66; I2=0%), followed by the MSS-TIL-H subtype for overall survival (HR 0·53, 0·41-0·69; I2=77·7%), disease-free survival (0·52, 0·41-0·64; I2=61·6%), and cancer-specific survival (0·55, 0·47-0·64; I2=0%) than did patients with MSS-TIL-low tumours (MSS-TIL-L). Patients with the MSI-TIL-L subtype had similar overall survival (0·88, 0·66-1·18; I2=77·7%) and disease-free survival (0·93, 0·69-1·26; I2=61·6%), but a modestly longer cancer-specific survival (0·72, 0·57-0·90; I2=0%) than did the MSS-TIL-L subtype. Results from the direct and indirect evidence were strongly congruous.
CONCLUSIONS: The findings from this network meta-analysis suggest that better survival was only observed among patients with TIL-H colorectal cancer, regardless of MSI or MSS status. The integrated MSI-TIL classification should be further explored as a predictive tool for clinical decision-making in early-stage colorectal cancer.
BACKGROUND: German Research Council (HO 5117/2-2).

OBJECTIVE: To determine the survival benefit and immunomodulatory effects of cimetidine pre-, peri- or post-operatively in patients with colorectal cancer (CRC).
METHODS: A systematic review was conducted using PubMed and Cochrane Library to retrieve randomized control trials (RCTs) that investigated the effects of cimetidine on survival and immunomodulation via improvement in tumor infiltrating lymphocytes (TILs) and peripheral blood lymphocytes. The review was carried out in accordance with the extended Preferred Reporting Items for Systematic Reviews and Meta-analyses.
RESULTS: Four studies with the total of 267 patients were included in this systematic review. Treatment duration varied from 5 days to 1 year. Two studies reported a significant TIL response in the resected specimens after administering cimetidine, while one RCT showed an escalation of CD3, CD4 and CD57 lymphocytes in peripheral blood compared to the baseline following cimetidine treatment (p < 0.01). Of the three trials that examined the effects of cimetidine on survival, only two studies revealed significant survival benefit while the remaining study only showed a trend towards survival benefit.
CONCLUSIONS: Repurposing of existing drugs like cimetidine has a potential to offer a survival benefit by acting as an immunomodulatory agent in patients undergoing curative resection for CRC. However, the heterogeneity seen in current studies and the evolvement of adjunctive therapies for CRC warrant large-scale, well-designed prospective RCTs to establish the efficacy of cimetidine in CRC.

The incidence of colorectal cancer (CRC), one of the deadliest cancers around the world, is increasing. Tissue microenvironment (TME) features such as tumor-infiltrating lymphocytes (TILs) can have a crucial impact on diagnosis or decision-making for treating patients with CRC. While clinical studies showed that TILs improve the host immune response, leading to a better prognosis, inter-observer agreement for quantifying TILs is not perfect. Incorporating machine learning (ML) based applications in clinical routine may promote diagnosis reliability. Recently, ML has shown potential for making progress in routine clinical procedures. We aim to systematically review the TILs analysis based on ML in CRC histological images. Deep learning (DL) and non-DL techniques can aid pathologists in identifying TILs, and automated TILs are associated with patient outcomes. However, a large multi-institutional CRC dataset with a diverse and multi-ethnic population is necessary to generalize ML methods.

Adoptive cell therapy with tumor-infiltrating lymphocytes (TIL) has demonstrated durable clinical responses in patients with metastatic melanoma, substantiated by recent positive results of the first phase III trial on TIL therapy. Being a demanding and logistically complex treatment, extensive preclinical and clinical effort is required to optimize patient selection by identifying predictive biomarkers of response. This review aims to comprehensively summarize the current evidence regarding the potential impact of tumor-related factors (such as mutational burden, neoantigen load, immune infiltration, status of oncogenic driver genes, and epigenetic modifications), patient characteristics (including disease burden and location, baseline cytokines and lactate dehydrogenase serum levels, human leucocyte antigen haplotype, or prior exposure to immune checkpoint inhibitors and other anticancer therapies), phenotypic features of the transferred T cells (mainly the total cell count, CD8:CD4 ratio, ex vivo culture time, expression of exhaustion markers, costimulatory signals, antitumor reactivity, and scope of target tumor-associated antigens), and other treatment-related factors (such as lymphodepleting chemotherapy and postinfusion administration of interleukin-2).

We aimed to assess the prognostic value of tumor infiltrating lymphocytes (TILs) in patients with bladder cancer (BC) after radical cystectomy (RC).
We searched Pubmed, Web of Science and Scopus in April 2022 to identify studies assessing the prognostic value of TILs, including a subset of lymphocytes (eg, CD3, CD8, FOXP3), after RC. The endpoints were overall survival and recurrent free survival. Subgroup analyses were performed based on the evaluation method for TILs (ie, CD3, CD8, FOXP3, HE staining).
Overall, 9 studies comprising 1413 patients were included in this meta-analysis. The meta-analysis revealed that elevated expressions of TILs were significantly associated with favorable OS (pooled hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.51-0.83) and RFS (pooled HR: 0.48, 95% CI: 0.35-0.64). In subgroup analyses, high CD8+ TILs were also associated with favorable OS (HR: 0.51, 95% CI: 0.33-0.80) and RFS (pooled HR: 0.53, 95% CI: 0.36-0.76). Among 3 studies comprising 146 patients, high intratumoral TILs were significantly associated with favorable OS (pooled HR: 0.34, 95% CI: 0.19-0.60).
TILs are useful prognostic markers in patients treated with RC for BC. Although the prognostic value of TILs is varied, depending on the subset and infiltration site, CD8+ TILs and intratumoral TILs are associated with oncologic outcomes. Further studies are warranted to explicate the predictive value of TILs on the response to perioperative systemic therapy to help clinical decision-making in patients with BC.

E2F transcription factors (E2Fs) are a group of genes that encode a family of transcription factors. They have been identified as being involved in the tumor progression of various cancer types. However, little is known about the expression level, genetic variation, molecular mechanism, and prognostic value and immune infiltration of different E2Fs in HNSCC.In this study, we utilized multiple databases to investigate the mRNA expression level, genetic alteration, and biological function of E2Fs in HNSCC patients. Then, the relationship between E2Fs expression and its association with the occurrence, progress, prognosis, and immune cell infiltration in patients with HNSCC was evaluated. We found that all eight E2Fs were higher expressed in HNSCC tissues than in normal tissues, and the expression levels of E2F1/2/3/4/5/6/8 were also associated with the stage and grade of HNSCC. The abnormal expression of E2F1/2/4/8 in HNSCC patients is related to the clinical outcome. The expression of E2Fs was statistically correlated with the immune cell infiltration in HNSCC and the infiltration of B cells and CD8+ T cells were positively associated with better OS in HNSCC patients. Furthermore, we verified the E2F2 at the tissue level in the validation experiment. Our study may provide novel insights into the choice of immunotherapy targets and potential prognostic biomarkers in HNSCC patients.

The microenvironment of diffuse large B-cell lymphoma (DLBCL) is composed of various components, including immune cells and immune checkpoints, some of which have been correlated with the prognosis of DLBCL, but their results remain controversial. Therefore, we conducted a systematic review and meta-analysis to investigate the association between the microenvironment and prognosis in DLBCL. We searched PubMed, Web of Science, and EMBASE for relevant articles between 2001 and 2022. Twenty-five studies involving 4495 patients with DLBCL were included in the analysis. This meta-analysis confirmed that high densities of Foxp3+Tregs and PD-1+T cells are good indicators for overall survival (OS) in DLBCL, while high densities of programmed cell death protein ligand1(PD-L1)-positive expression cells and T-cell immunoglobulin-and mucin domain-3-containing molecule 3 (TIM-3)-positive expression tumor-infiltrating cells (TILs) play a contrary role in OS. Additionally, higher numbers of T-cell intracytoplasmic antigen-1(TIA-1)-positive expression T cells imply better OS and progression-free survival (PFS), while high numbers of lymphocyte activation gene(LAG)-positive expression TILs predict bad OS and PFS. Various non-tumoral cells in the microenvironment play important roles in the prognosis of DLBCL.

BACKGROUND: This study aimed to explore the value of tumor-infiltrating Forkhead box P3(FoxP3+) regulatory T cells (Tregs) in evaluating the prognosis of biliary tract cancer.
METHODS: Four electronic databases were searched using 2 computers: PubMed, Embase, Web of Science, and Cochrane Library. The vocabulary and syntax were adapted according to the database. Two researchers independently selected the studies, collected information, and assessed the risk of bias. The Meta-analysis was performed using STATA 17.0, and HR and its corresponding 95% CI were used to evaluate the correlation between FoxP3+ Tregs and the overall survival of patients with biliary tract cancer. In addition, the quality of the included studies was evaluated.
RESULTS: Ten articles were included in this study. The results of the meta-analysis showed that patients with high FoxP3+ Tregs infiltration had worse overall survival (OS) (HR = 1.34,95% CI 1.16 to 1.71; P < .001). Subgroup analysis of gallbladder carcinoma and cholangiocarcinoma showed that the high infiltration of FoxP3+ Tregs was significantly correlated with the OS of the former (HR = 1.55,95% CI 1.11 to 2.00; P < .001), but not with the OS of the latter (HR = 1.00,95% CI 0.62 to 1.38; P > .05).
CONCLUSIONS: Our meta-analysis reveals that high infiltration of FoxP3 + Tregs is significantly associated with reduced overall survival in gallbladder carcinoma, endorsing their use as a prognostic biomarker for this subtype. In contrast, no significant prognostic correlation was identified for FoxP3+ Tregs in cholangiocarcinoma, indicating the need for subtype-specific evaluation of their prognostic relevance in biliary tract cancers.

Gastrointestinal (GI) cancers remain a significant global health burden, accounting for a substantial number of cases and deaths. Regrettably, the inadequacy of dependable biomarkers hinders the precise forecasting of patient prognosis and the selection of appropriate therapeutic sequencing for individuals with GI cancers, leading to suboptimal outcomes for numerous patients. The intricate interplay between tumor-infiltrating lymphocytes (TILs) and the tumor immune microenvironment (TIME) has been shown to be a pivotal determinant of response to anti-cancer therapy and consequential clinical outcomes across a multitude of cancer types. Therefore, the assessment of TILs has garnered global interest as a promising prognostic biomarker in oncology, with the potential to improve clinical decision-making substantially. Moreover, recent discoveries in immunotherapy have progressively changed the landscape of cancer treatment and significantly prolonged the survival of patients with advanced cancers. Nonetheless, the response rate remains constrained within solid tumor sufferers, even when TIL landscapes appear comparable, which calls for the development of our understanding of cellular and molecular cross-talk between TIME and tumor. Hence, this comprehensive review encapsulates the extant literature elucidating the TILs\' underlying molecular pathogenesis, prognostic significance, and their relevance in the realm of immunotherapy for patients afflicted by GI tract cancers. Within this review, we demonstrate that the type, density, and spatial distribution of distinct TIL subpopulations carries pivotal implications for the prediction of anti-cancer treatment responses and patient survival. Furthermore, this review underscores the indispensable role of TILs in modulating therapeutic responses within distinct molecular subtypes, such as those characterized by microsatellite stability or programmed cell death ligand-1 expression in GI tract cancers. The review concludes by outlining future directions in TIL-based personalized medicine, including integrating TIL-based approaches into existing treatment regimens and developing novel therapeutic strategies that exploit the unique properties of TILs and their potential as a promising avenue for personalized cancer treatment.