Density Of Tumor-infiltrating Lymphocytes Research Articles

Pan-immune-inflammation value predicts immunotherapy response and reflects local antitumor immune response in rectal cancer.

The pan-immune-inflammation value reflects the systemic inflammatory response, and tumor-infiltrating lymphocytes indicate a local immune response in rectal cancer. However, the association between systemic inflammatory response, as indicated by the pan-immune-inflammation value, and local immune responses in rectal cancer remains unclear. This study analyzed 915 treatment-naïve rectal cancer patients from the Peking Union Medical College Hospital and PLA General Hospital (PLAGH) cohorts who underwent radical surgery to investigate the relationship between the pan-immune-inflammation value and immune responses. Lower pan-immune-inflammation value was significantly associated with improved disease-free survival and cancer-specific survival. Multivariate Cox regression models identified the pan-immune-inflammation value as an independent prognostic factor. In the PLAGH cohort, patients with low pan-immune-inflammation values had higher immune cell levels, activated immune pathways, and increased expression of immune checkpoint genes according to RNA sequencing. Hematoxylin and eosin staining and immunohistochemical analysis revealed that lower pan-immune-inflammation value was associated with higher tumor-infiltrating lymphocyte density, more mature tertiary lymphoid structures, increased CD8+ T cells, and elevated human lymphocyte antigen class I expression. Conversely, patients with high pan-immune-inflammation values exhibited pathways linked to tumor progression, such as angiogenesis, epithelial-mesenchymal transition, hypoxia, KRAS signaling, and TGF-ß signaling. Among patients receiving anti-PD-1 therapy, responders had low pre- and post-treatment pan-immune-inflammation values. The pan-immune-inflammation value is a reliable marker associated with distinct immune microenvironment characteristics and can effectively predict disease-free survival, cancer-specific survival, and response to immunotherapy.

Prognostic significance of CD8 and TCF1 double positive T cell subset in microsatellite unstable gastric cancer

Microsatellite instability-high (MSI-H) gastric cancer (GC) exhibits high tumor-infiltrating lymphocyte (TIL) density. Despite the recognized significance of the immune microenvironment in MSI-H GC, our understanding of TIL remains limited. This study aimed to investigate the clinicopathologic and prognostic implications of T cell subsets in MSI-H GC. Single immunohistochemistry (IHC) for CD8, TCF1, and CD103, and double IHC for CD8/TCF1 and CD8/CD103 were performed in 382 surgically resected MSI-H GC samples. Densities of single or double positive immune cells were quantified and correlated with clinicopathologic features and overall survival (OS). TCF1 + cell densities showed weak correlations with CD8 + and CD103 + cell densities, while CD8+/TCF1 + cell density moderately correlated with CD8+/CD103 + cell density (R2 = 0.539, p < 0.001). Single IHC analyses showed no significant associations between CD8+, TCF1+, or CD103 + cell densities and OS (p > 0.05). Notably, elevated CD8+/TCF1 + cell density and a high CD8+/TCF1 + to CD8 + ratio correlated with less aggressive clinicopathologic features and improved OS (p = 0.017 and 0.001, respectively). Multivariable Cox-regression identified CD8+/TCF1 + to CD8 + ratio as an independent prognostic factor (p = 0.028). We demonstrated the prognostic significance of CD8+/TCF1 + to CD8 + ratio using double IHC in a large cohort of MSI-H GC.

Changes in the tumor microenvironment in recurrent head and neck squamous cell carcinoma and its implication on efficacy of immune checkpoint inhibitors

Little is known about changes in the abundance of tumor-infiltrating lymphocytes (TILs) and immune phenotype (IP) in recurrent and/or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). We aimed to compare the TILs and IP between initial and recurrent HNSCCs using paired analysis. Thirty-seven patients who experienced recurrence after surgical resection and received treatment with immune checkpoint inhibitors (ICIs) between June 2014 and June 2023 were included. Changes in intratumoral TIL (iTILs), stromal TIL (sTILs), and IPs were subjected to paired analysis between the initial and recurrent tumors. We investigated their relationship with the outcomes of ICIs. The density of iTIL and sTIL in the recurrent tumors was significantly lower compared to initial tumors. IP was significantly different; the proportion of desert IP was higher in recurrent tumors (83.8% vs. 35.1%, P < 0.001). Increased sTIL was a favorable indicator for overall response to ICIs and progression-free survival. Our findings suggest TILs decrease during recurrence compared with the initial tumor, resulting in a transition toward desert IP. Therefore, careful evaluation of TIL density in both initial and recurrent tumors is recommended when using ICIs in patients with R/M HNSCC.

The prognostic value of tumor-infiltrating lymphocytes in vulvovaginal melanoma

ObjectiveTo assess the relation between immune microenvironment, survival, and clinicopathological characteristics.MethodsThis study was a retrospective, single-center, observational study. Patients with a vulvovaginal melanoma and available archived material were included. All...

Machine learning-driven estimation of mutational burden highlights DNAH5 as a prognostic marker in colorectal cancer

BackgroundTumor Mutational Burden (TMB) have emerged as pivotal predictive biomarkers in determining prognosis and response to immunotherapy in colorectal cancer (CRC) patients. While Whole Exome Sequencing (WES) stands as the gold standard for TMB assessment, carry substantial costs and demand considerable time commitments. Additionally, the heterogeneity among high-TMB patients remains poorly characterized.MethodsWe employed eight advanced machine learning algorithms to develop gene-panel-based models for TMB estimation. To rigorously compare and validate these TMB estimation models, four external cohorts, involving 1,956 patients, were used. Furthermore, we computed the Pearson correlation coefficient between the estimated TMB and tumor neoantigen levels to elucidate their association. CD8+ tumor-infiltrating lymphocyte (TIL) density was assessed via immunohistochemistry.ResultsThe TMB estimation model based on the Lasso algorithm, incorporating 20 genes, exhibiting satisfactory performance across multiple independent cohorts (R2 ≥ 0.859). This 20-gene TMB model proved to be an independent prognostic indicator for the progression-free survival (PFS) of CRC patients (p = 0.001). DNAH5 mutations were associated with a more favorable prognosis in high-TMB CRC patients, and correlated strongly with tumor neoantigen levels and CD8+ TIL density.ConclusionsThe 20-gene model offers a cost-efficient approach to precisely estimating TMB, providing prognosis in patients with CRC. Incorporating DNAH5 within this model further refines the categorization of patients with elevated TMB. Utilizing the 20-gene model facilitates the stratification of patients with CRC, enabling more precise treatment planning.

Tumor-Infiltrating B Cells and Tissue-Resident Memory T Cells as Prognostic Indicators in Brain Metastases Derived from Gastrointestinal Cancers.

Tumor-infiltrating B cells (TIBs) and tissue-resident memory T cells (TRMs) play significant roles in antitumor immunity. However, their prognostic relevance in brain metastases (BMs) derived from gastrointestinal (GI) cancers remains unclear. This study aimed to investigate the prognostic significance of TIBs and TRMs in GI cancer-derived BMs (GIBMs). Retrospective histopathological analyses were performed on surgically resected GIBM tissues from 13 patients. The densities of tumor-infiltrating lymphocytes (TIL) subsets (TIBs, CD4+ T cells, CD8+CD103+ TRMs, and CD8+CD103- non-TRMs) were quantified and correlated with clinical parameters and overall survival (OS) including the Graded Prognostic Assessment (GPA). TIBs and CD4+ T cells were predominantly accumulated in the tumor stroma, particularly around blood vessels, where they formed lymphocyte clusters without characteristics of tertiary lymphoid structures (TLSs). In contrast, TRMs more deeply infiltrated into the tumor epithelium than their counterpart non-TRMs. Positive correlations were found between TIB density and both the prognostic prediction of GPA and overall survival (OS) after BM diagnosis or surgery. Furthermore, increased densities of TIBs and TRMs were associated with enhanced survival after BM diagnosis. TIB and TRM densities in BM tissues could serve as reliable prognostic indicators for survival in patients with GIBMs. This study provides crucial insights for the development of novel immunotherapeutic strategies against this lethal disease.

AI-based tumor-infiltrating lymphocytes scoring system for assessing HCC prognosis in patients undergoing liver resection

Background & AimsTumor-infiltrating lymphocytes (TILs), particularly CD8+ TILs, are key prognostic markers in many cancers. However, their prognostic value in hepatocellular carcinoma (HCC) remains controversial, with different evidence. Given the heterogeneous outcomes in HCC patients undergoing liver resection, this study aims to develop an AI-based system to quantify CD8+ TILs and assess their prognostic value for HCC patients. MethodsWe conducted a retrospective multicenter study on patients undergoing liver resection across three cohorts (N=514). We trained a deep neural network and a random forest model to segment tumor regions and locate CD8+ TILs in H&E and CD8-stained whole slide images (WSIs). We quantified CD8+ TIL density and established an Automated CD8+ Tumor-infiltrating Lymphocyte Scoring (ATLS-8) system to assess its prognostic value. ResultsIn discovery cohort, the 5-year overall survival (OS) rates were 34.05% for ATLS-8 low-score and 65.03% for ATLS-8 high-score groups (HR 2.40; 95% CI, 1.37–4.19; P = 0.015). These findings were confirmed in validation cohort 1, which had 5-year OS rates of 28.57% and 68.73% (HR 3.38; 95% CI, 1.27–9.02; P = 0.0098), and validation cohort 2, which had 59.26% and 81.48% (HR 2.74; 95% CI, 1.05–7.15; P = 0.031). ATLS-8 improved prognostic model based on clinical variables (C-index 0.770 vs. 0.757; 0.769 vs. 0.727; 0.712 vs. 0.642 in three cohorts). ConclusionWe developed an automated system using CD8-stained WSIs to assess immune infiltration (ATLS-8). In HCC patients undergoing resection, higher CD8+ TIL density correlates with better OS, as per ATLS-8 assessment. This system is a promising tool for advancing clinical immune microenvironment assessment and outcome prediction. Impact and implicationCD8+ TILs have been identified as a prognostic factor associated with many cancers. In this study, CD8+ TILs were identified as an independent prognostic factor for OS in patients with hepatocellular carcinoma who undergoing liver resection. Therefore, ATLS-8, a novel digital biomarker based on WSI-level CD8+ TILs, could play an important role in the prognostic assessment of HCC patients and could be integrated into clinicopathological models to participate in the decision-making and prognostic assessment of patients. The scoring system combined with artificial intelligence is essential for automated, quantitative, WSI- level assessment of TILs, which can be widely applied to quantify the immune profile of multi-cancer disease types with the discussion of subsequent immunotherapy. Clinical trial numberThis is a retrospective study and does not require a clinical trial number.

The combination of CDX2 expression status and tumor-infiltrating lymphocyte density as a prognostic factor in adjuvant FOLFOX-treated patients with stage III colorectal cancers.

Colorectal carcinomas (CRCs) with caudal-type homeobox 2 (CDX2) loss are recognized to pursue an aggressive behavior but tend to be accompanied by a high density of tumor-infiltrating lymphocytes (TILs). However, little is known about whether there is an interplay between CDX2 loss and TIL density in the survival of patients with CRC. Stage III CRC tissues were assessed for CDX2 loss using immunohistochemistry and analyzed for their densities of CD8 TILs in both intraepithelial (iTILs) and stromal areas using a machine learning-based analytic method. CDX2 loss was significantly associated with a higher density of CD8 TILs in both intraepithelial and stromal areas. Both CDX2 loss and a high CD8 iTIL density were found to be prognostic parameters and showed hazard ratios of 2.314 (1.050-5.100) and 0.378 (0.175-0.817), respectively, for cancer-specific survival. A subset of CRCs with retained CDX2 expression and a high density of CD8 iTILs showed the best clinical outcome (hazard ratio of 0.138 [0.023-0.826]), whereas a subset with CDX2 loss and a high density of CD8 iTILs exhibited the worst clinical outcome (15.781 [3.939-63.230]). Altogether, a high density of CD8 iTILs did not make a difference in the survival of patients with CRC with CDX2 loss. The combination of CDX2 expression and intraepithelial CD8 TIL density was an independent prognostic marker in adjuvant chemotherapy-treated patients with stage III CRC.

Phase 2 trial of avelumab in combination with gemcitabine in advanced leiomyosarcoma as a second-line treatment (EAGLES, Korean Cancer Study Group UN18-09).

In this single-arm, multicenter, phase 2 trial, the authors evaluated the efficacy and safety of avelumab plus gemcitabine in patients with leiomyosarcoma (LMS) who failed on first-line chemotherapy. Patients with advanced LMS received avelumab 10 mg/kg on days 1 and 15 (for up to 24 months) plus gemcitabine 1000 mg/m2 on days 1, 8, and 15 of a 28-day cycle until they developed disease progression or intolerable toxicity. The primary end point was the objective response rate (ORR). In total, 38 patients were enrolled. Of these, 35 patients were evaluable, and the ORR was 20% (95% confidence interval; [CI], 8%-37%). The disease control rate was 71%, and the median duration of response was 21.8 months (range, 7.6 to ≥43.3 months). The median progression free-survival was 5.6 months (95% CI, 4.5-6.8 months), and the median overall survival was 27.5 months (95% CI, 20.4-34.6 months). Grade 3-4 adverse events occurred in 70% of patients, of which neutropenia was the most common (54%). Immune-mediated adverse events occurred in five patients (14%; hypothyroidism, n=3; hepatitis, n=2). Patients who had a higher density of tumor-infiltrating lymphocytes (greater than the median) exhibited better ORR (35% vs. 8%; p=.104), progression-free survival (median, 7.3 vs. 3.3 months; p=.024), and overall survival (median, not reached vs. 21.5 months; p=.027). The combination of avelumab and gemcitabine demonstrated promising efficacy and manageable safety in patients with advanced LMS who progressed on first-line therapy. Tumor-infiltrating lymphocyte density may be an important factor in predicting the response to combining immunotherapy with chemotherapy.

Assessment of PD-L1 expression and tumour infiltrating lymphocytes in early-stage non-small cell lung carcinoma with artificial intelligence algorithms

AimsTo study programmed death ligand 1 (PD-L1) expression and tumour infiltrating lymphocytes (TILs) in patients with early-stage non-small cell lung carcinoma (NSCLC) with artificial intelligence (AI) algorithms.MethodsThe study included samples...

Lower expressions of MIR34A and MIR31 in colo-rectal cancer are associated with an enriched immune microenvironment

IntroductionMicroRNAs (MIRs) play a crucial role in colorectal cancer (CRC) development and metastasis by regulating immune responses. Tumour-infiltrating lymphocytes (TILs) are an important predictive factor in many cancers, but, their association with microRNAs have not been studied well in colorectal cancer. Three microRNAs (MIR34A, MIR31 & MIR21), the roles of which in tumorigenesis is well-studied and which also possess immunomodulatory effect, were identified by extensive literature search. Of these, MIR34A acts as a tumour suppressor, MIR21 is considered an onco-MIR, and MIR31 displays both tumour-suppressing and oncogenic properties, making it ambiguous. This study examines the relationship between these three micro-RNAs and TILs in CRC. Materials & methodsConducted over 18 months at a tertiary cancer care hospital in southern India, this unicentric observational study included 69 cases. These cases were analyzed for miR expression using q-RT-PCR, TILs density through hematoxylin & eosin(H&E) slide examination, and p53 and beta-catenin expression via immunohistochemistry (IHC). Correlations between non-parametric variables were assessed using Chi-square and Spearman correlation tests. ResultsThe study found significantly higher MIR34A expression in patients aged 60 years and less (26/41, p=0.024) and a higher prevalence of MIR21 in male patients (23/35, p=0.012). TILs at the tumour advancing front were categorized as low (≤10 %) or high (≥15 %). Among the 36 cases with low TILs, high MIR34A and high MIR31 expressions were observed in 24 cases (p=0.016) and 23 cases (p=0.03), respectively. Conversely, 21 of 33 cases with high TILs had low expressions of both MIR34A and MIR31. High TILs were more common in early-stage CRC (TNM stages I-IIIA), with 20 out of 28 cases, compared to 28 of 41 cases in later stages (IIIB-IVC) exhibiting low TILs (p=0.003). Aberrant p53 expression correlated with lower MIR34A levels, consistent with TCGA data. ConclusionLower MIR34A and MIR31 levels are associated with higher TILs density in CRC. Unlike other cancers where MIR34A has anti-tumour effects, there was no statistically significant correlation between its expression and the pT or TNM stages in this study. Increased TILs being a good prognostic indicator, this suggests MIR34A and MIR31 may help CRC cells evade immune surveillance. Aberrant p53 expression downregulates MIR34A, underscoring the therapeutic potential of miRs.

Relationships between tumor CD147 expression, tumor-infiltrating lymphocytes, and oncostatin M in hepatocellular carcinoma.

In hepatocellular carcinoma (HCC), CD147 expression contributes to tumor malignancy; however, its relationship with the tumor-immune microenvironment (TIME) remains unclear. This study aimed to elucidate the clinicopathological characteristics associated with CD147 expression in HCC and investigate its association with the TIME, specifically its association with tumor-infiltrating lymphocytes (TILs) and oncostatin M (OSM). Using 397 HCC specimens from patients undergoing curative-intent resection, we assessed CD147 expression in tumor cells and quantified OSM-positive cells and various TILs (CD8+, CD4+, FOXP3+, and CD20+ cells) in the TIME. Using tissue microarrays, these assessments were performed through immunohistochemical analysis. We investigated the associations between CD147 expression status, the density of OSM-positive cells, and the densities of various TILs. High CD147 expression, found in 332 specimens (83.6%), was associated with advanced clinical stage (P = 0.029), fibrosis (P = 0.036), and higher densities of FOXP3+ cells (P = 0.0039), CD4+ cells (P = 0.0012), and OSM-positive cells (P = 0.0017). In CD147-high tumors, OSM-positive cell density was associated with all assessed TIL subsets (CD8+, CD4+, FOXP3+, and CD20+ cells; all Ps < 0.001), whereas in CD147-low tumors, OSM-positive cell density was associated only with FOXP3+ cells (P = 0.0004). In HCC, CD147 expression is associated with an immunosuppressive TIME, characterized by increased FOXP3+ regulatory T cells and a correlation with OSM-positive cells. These results elucidate the potential mechanisms through which CD147 facilitates tumor-immune evasion, suggesting the CD147 - OSM axis as a promising target for therapeutic intervention in HCC.

Intratumoral T cells are associated with prognosis and chemotherapy benefit in gastric cancer.

Tumor-infiltrating lymphocytes (TILs) have been described in various malignancies and viewed as a sign of anti-tumor immunity, so they are frequently thought to be implicated in the prognosis of cancers. However, little information is available on the association of the distribution pattern of TILs with clinical outcomes in gastric cancer (GC). TIL densities at different regions were assessed immunohistochemically in 59 GC patients to analyze their relationship with clinicopathological characteristics. We found that GC patients in the high-density TIL group were significantly associated with reduced tumor invasion depth, absence of lymph node metastasis, earlier TNM stage, and improved progression-free survival (PFS). Both intratumoral CD3+ TILs and pathological T stage were identified as having an independent prognostic value. Additionally, GC patients with a high density of intratumoral CD3+ TILs were found to gain more benefit from chemotherapy. Overall, these results underscored the predictive power of intratumoral TILs in survival prognosis and chemotherapy benefit for GC.

Role of Ultrasonographic and Clinicopathological Characteristics in Assessing Stromal Tumor-Infiltrating Lymphocyte Density in Triple-Negative Breast Cancer

A high density of stromal tumor-infiltrating lymphocytes (sTILs) is positively correlated with the pathological complete response rate and favorable survival in patients with triple-negative breast cancer (TNBC). Heterogeneity in stromal lymphocyte distribution and limited tumor sampling may affect the accuracy of sTIL quantification in biopsy samples from patients receiving neoadjuvant therapy. Thus, identifying additional biomarkers to complement sTIL evaluation is essential. To identify biomarkers that could be used to complement sTILs evaluation. Retrospective cohort study. A total of 162 patients with invasive TNBC were enrolled in the study. The following data were gathered: sTIL density, Ki67, nuclear grades of cancer cells, lymphovascular invasion status, the American Joint Committee on Cancer stage, axillary lymph node metastasis status, and ultrasonographic parameters of the tumor (size, shape, orientation, margin, internal echo pattern, posterior feature, and vascularity). The relationship between sTIL density and ultrasonographic or clinicopathological characteristics was investigated using both continuous and categorical analyses. Posterior features of the primary tumors was associated with sTIL density (p = 0.038). Additionally, the Ki67 levels and nuclear grades were also associated with sTIL density (p < 0.001 and p = 0.024, respectively). When stratified according to a 20% cut-off of sTIL density, the posterior features of primary tumors, Ki67 levels, and nuclear grades significantly differed between the high and low sTIL density tumors. Tumors with high Ki67 levels were more likely to exhibit high sTIL density than low sTIL density [odds ratio (OR): 2.75, p = 0.021]. Furthermore, nuclear grade III tumors demonstrated significantly higher sTIL density than nuclear grade I-II tumors (OR: 2.49, p = 0.014). Additionally, tumors with posterior enhancement or no posterior features were more likely to exhibit high sTIL density than tumors with acoustic shadows (OR: 2.91, p = 0.028; OR: 2.74, p = 0.022, respectively). Low sTIL density is frequently observed in tumors exhibiting acoustic shadows on ultrasound. However, high sTIL density is more common in tumors with posterior enhancement or no posterior features. Furthermore, high Ki67 levels (> 40%) and high nuclear grades are positively correlated with high sTIL density. This study findings highlight the need for closer surveillance of these biomarkers to complement sTIL evaluation in TNBC.

MCT4 is an independent prognostic factor and affects immune cell infiltration in patients with colorectal liver oligometastases.

Monocarboxylate transporter 4 (MCT4) is a novel biomarker related to the level of immune cell infiltration, but its impact on tumor immune microenvironment (TIME) of colorectal liver oligometastases (CLO) remains unclear. The aim of this study was to assess MCT4 expression in primary tumor and liver oligometastases, investigate its impact on immune cell infiltration and its prognostic value for CLO patients undergoing liver resection. We retrospectively selected 135 CLO patients who underwent curative liver resection between June 1999 and December 2016, and samples included 74 primary tumor tissues and 122 liver metastases. Immunohistochemistry (IHC) was performed to detect MCT4 expression in paraffin-embedded specimens and tyramine signal amplification (TSA) was used to detect the density of tumor-infiltrating lymphocytes, including CD3 + , CD8 + and Foxp3 + . Recurrence-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and log-rank test, and independent prognostic factors were identified with Cox regression modeling. Survival analysis indicated that CLO patients with low MCT4 expression had better 3-year RFS and 3-year OS rates than those with high MCT4 expression. Multivariate analysis indicated that high MCT4 expression was independently associated with poor RFS and OS. High MCT4 expression was associated with a lower number of intratumoral CD3 + /CD8 + T cells and was associated with higher Foxp3 + T cells infiltration. Patients with low MCT4 expression and high levels of differential immune infiltration had longer survival. MCT4 overexpression was associated with an unfavorable prognosis in patients with CLO and MCT4 expression level had an impact on intratumoral immune infiltration degree. A novel parameter that combined MCT4 expression level and differential immune infiltration level was constructed to stratify patients with CLO into different risk groups.

Characterization of pre- and on-treatment soluble immune mediators and the tumor microenvironment in NSCLC patients receiving PD-1/L1 inhibitor monotherapy

BackgroundDespite the favorable therapeutic efficacy observed with ICI monotherapy, the majority of non-small cell lung cancer (NSCLC) patients do not respond. Therefore, identifying patients who could optimally benefit from ICI treatment remains a challenge.MethodsAmong 183 patients with advanced or recurrent NSCLC who received ICI monotherapy, we analyzed 110 patients whose pre- and post-treatment plasma samples were available. Seventy-three soluble immune mediators were measured at ICI initiation and 6 weeks later. To identify useful biomarkers, we analyzed the association of pre-treatment levels and on-treatment changes of soluble immune mediators with survival of patients. The associations of pre-treatment or on-treatment biomarkers with irAE development, PD-L1 expression, CD8+ TIL density, and neutrophil to lymphocyte ratio (NLR) were also analyzed.ResultsUnivariate analysis showed that pre-treatment biomarkers included 6 immune mediators, whereas on-treatment biomarkers included 8 immune mediators. Multivariate analysis showed that pre-treatment biomarkers included 4 immune mediators (CCL19, CCL21, CXCL5, CXCL10), whereas on-treatment biomarkers included 5 immune mediators (CCL7, CCL19, CCL23, CCL25, IL-32). IrAE development was associated with on-treatment change in CCL23. PD-L1 expression was associated with the pre-treatment levels of TNFSF13B and the on-treatment change in CCL25. CD8+ TIL density was associated with the pre-treatment CXCL10 level, whereas NLR was correlated with pre-treatment levels of CCL13 and CCL17.ConclusionWe identified several soluble immune mediators as pre-treatment and on-treatment biomarkers of survival in patients with NSCLC treated with ICI monotherapy. Some of these biomarkers were associated with other possible predictors, including irAE development, PD-L1 expression, CD8+ TIL density and NLR. Further large-scale studies are needed to establish biomarkers for patients with NSCLC who received ICI monotherapy.

587. PD-L1 EXPRESSION AND CD8+ TUMOR-INFILTRATING LYMPHOCYTES CHANGES AFTER PREOPERATIVE CHEMORADIOTHERAPY IN ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Abstract Background Neoadjuvant chemoradiotherapy (nCRT) has been established as a standard treatment for locally advanced esophageal squamous cell carcinoma (SqCC), but there are still insufficient research advances on the incorporation of immunologic agents. The aim of this study was to explore immune microenvironment changes before and after nCRT. Methods A total of 101 patients who underwent nCRT followed by radical surgery for esophageal SqCC in a single institution between 2005 and 2021 were analyzed. Pre-nCRT endoscopic biopsy and post-nCRT surgical specimen were evaluated using tissue microarray. Immunohistochemical staining for CD3, CD8, and PD-L1 were performed. Tumor-infiltrating lymphocytes (TIL) density were independently evaluated by blinded pathologist (total number of 2+ to 3+ cells/total area (mm2)). Results Compared to pre-nCRT biopsy, PD-L1 expression (8.7% vs. 14.0%, p&amp;lt;0.001) and TIL density (259.1 vs. 566.9, p&amp;lt;0.001) were significantly increased in surgical specimen after nCRT. When divided into groups according to nCRT response, post-nCRT TIL density (p=0.341), fold changes of TIL density (p=0.749), and PD-L1 expression (p=0.642) were not significantly different between ypCR (n=23) and non-ypCR group (n=78). In ypT0 group (n=36), post-nCRT TIL density was marginally higher than that of non-ypT0 group (404 vs. 259, p = 0.050). Conclusion Irrespective of clinical responses, PD-L1 expression and TIL density were both increased after nCRT. Our results could help the development of combination strategy of immunologic drugs and seek the possibility of an organ-saving strategy that will contribute to improving quality of life of patients.

Cancer immunoediting, PD-L1 expression, CTLA-4 and CD8+ tumor-infiltrating lymphocyte density, and chemoradiotherapy in nasopharyngeal carcinoma

Cancer immunoediting, PD-L1 expression, CTLA-4 and CD8+ tumor-infiltrating lymphocyte density, and chemoradiotherapy in nasopharyngeal carcinoma

Correlation of enriched specific subset of immune cells nearby tumor associated macrophage (TAM) with pathologic complete response (pCR) of concurrent chemoradiotherapy followed by nivolumab in locally advanced rectal cancer (LARC).

58 Background: We previously reported tumor-infiltrating lymphocyte (TIL) dynamics predictive of pCR in microsatellite-stable (MSS) LARC. In the current analysis, we investigate whether an immune cell-to-cell spatial network may predict pCR in MSS LARC. Methods: VOLTAGE study is a phase I/II study to evaluate the efficacy of chemoradiotherapy (CRT) followed by nivolumab and subsequent surgery in LARC pts. H&amp;E images and multiplex immunofluorescence (mIF) images containing a total of 35 markers for T cells, TAM, Myeloid-derived suppressor cells, and Dendritic cells were analyzed with the Lunit SCOPE platform (Lunit, Republic of Korea). The proportion of T cells among all DAPI-positive (-pos) cells in a 50-micrometer radius centered on the TAM cells was counted. Results: In the samples of MSS LARC pts gathered at baseline, pre-treatment (n=38), TIL density in tumor microenvironment (TME) analyzed by H&amp;E images was significantly correlated with the proportions of CD8-pos, CD4-pos, and FOXP3-pos cells (coefficient [coeff] 0.635, 0.482, and 0.580, respectively), but loosely correlated with PDL1-pos, PD1-pos, and CTLA4-pos cells (coeff 0.255, 0.174, and 0.180, respectively). Interestingly, intratumoral TIL density was more strongly correlated with TAM markers such as CD68 (coeff 0.269), compared to stromal TIL density (coeff 0.086). pCR rate was 28.9% in all MSS LARC, with baseline TIL density in TME predicting pCR with area under the receiver operating characteristic curve (AUROC) of 0.636 (p = 0.101). Interestingly, the ratio of baseline PDL1-pos cell proportion nearby CD68-pos cells, over that in all TME area (hereafter referred to as 'TAM-PDL1-proximity score') showed the best predictive performance for pCR, with an AUROC of 0.768 (p = 0.005). At the optimal cutoff of 1.66 times TAM-PDL1-proximity score, pCR rates for pts ≥ the cutoff and &lt; the cutoff were 44% (11/25) and 0% (0/13), respectively (p = 0.006). Conclusions: PDL1-expressing immune cells nearby tumor associated macrophages before treatment is a promising predictive biomarker for pCR of neoadjuvant CRT followed by nivolumab in MSS LARC.

Tertiary Lymphoid Structures in Brain Metastases of Lung Cancer: Prognostic Significance and Correlation With Clinical Outcomes.

The prognosis of patients with brain metastases (BMs) originating from lung cancer remains poor, despite advancements in treatment strategies. The role of tertiary lymphoid structures (TLSs) within the tumor immune microenvironment of BMs has not been extensively explored. This study utilized patient-derived clinical samples from 17 patients with histologically confirmed BMs of lung cancer, undergoing surgical resection. Immunohistochemistry was employed to analyze the presence and characteristics of TLS and tumor-infiltrating lymphocytes (TILs) within BM tissues, correlating these with clinical outcomes. TLSs, albeit in their immature form, were identified within BM tissues, distinguishing them from their mature counterparts in primary lung cancer tissues. A significant correlation between TLS density (but not TIL density) and improved postoperative survival was observed, underscoring the potential of TLS density as an independent prognostic marker. Furthermore, TLS density did not correlate with the Graded Prognostic Assessment (GPA) index, suggesting its unique prognostic value beyond conventional predictors. Our findings reveal the presence of TLSs in lung cancer-derived BMs and highlight their prognostic significance, independent of the GPA index. The identification of TLS within the unique central nervous system tumor microenvironment offers new insights into the immune landscape of BMs and suggests potential avenues for immunotherapeutic interventions targeting these structures to improve patient outcomes.