Tumor immunological characterization includes evaluation of tumor-infiltrating lymphocytes (TILs) and programmed cell death protein ligand-1 (PD-L1) expression. This study investigated TIL distribution, its prognostic value, and PD-L1 expression in metastatic and matched primary tumors (PTs). Specimens from 550 pan-cancer patients of the SHIVA01 trial (NCT01771458) with available metastatic biopsy and 111 matched PTs were evaluated for TILs and PD-L1. Combined positive score (CPS), tumor proportion score (TPS), and immune cell (IC) score were determined. TILs and PD-L1 were assessed according to PT organ of origin, histological subtype, and metastatic biopsy site. We found that TIL distribution in metastases did not vary according to PT organ of origin, histological subtype, or metastatic biopsy site, with a median of 10% (range: 0-70). TILs were decreased in metastases compared to PT (20% [5-60] versus 10% [0-40], p < 0.0001). CPS varied according to histological subtype (p = 0.02) and biopsy site (p < 0.02). TPS varied according to PT organ of origin (p = 0.003), histological subtype (p = 0.0004), and metastatic biopsy site (p = 0.00004). TPS was higher in metastases than in PT (p < 0.0001). TILs in metastases did not correlate with overall survival. In conclusion, metastases harbored fewer TILs than matched PT, regardless of PT organ of origin, histological subtype, and metastatic biopsy site. PD-L1 expression increased with disease progression. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

OBJECTIVE: Tumor-infiltrating lymphocytes (TILs) represent a host-tumor interaction, frequently signifying an augmented immunological response. Nonetheless, implications with survival outcomes in patients with colorectal carcinoma liver metastasis (CRLM) warrant rigorous validation. The objective was to demonstrate the association between TILs and survival in patients with CRLM.
METHODS: In a retrospective evaluation conducted in a single institution, we assessed all patients who underwent hepatectomy due to CRLM between 2014 and 2018. Comprehensive medical documentation reviews were executed. TILs were assessed by a liver pathologist, blinded to the clinical information, in all surgical slides.
RESULTS: This retrospective cohort included 112 patients. Median overall survival (OS) was 58 months and disease-free survival (DFS) was 12 months for the entire cohort. Comparison between groups showed a median OS of 81 months in the dense TILs group and 40 months in the weak/absent group (p = 0.001), and DFS was 14 months versus 9 months (p = 0.041). Multivariable analysis showed that TILs were an independent predictor of OS (HR 1.95; p = 0.031).
CONCLUSIONS: Dense TILs are a pivotal prognostic indicator, correlating with enhanced OS. Including TILs information in histopathological evaluations should refine the clinical decision-making process for this group of patients.

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Adoptive cell therapy (ACT) is a rapidly growing anti-cancer strategy that has shown promise in treating various cancer types. The concept of ACT involves activating patients\' own immune cells ex vivo and then transferring them back to the patients to recognize and eliminate cancer cells. Currently, the commonly used ACT includes tumor-infiltrating lymphocytes (TILs), genetically engineered immune cells, and dendritic cells (DCs) vaccines. With the advancement of cell culture and genetic engineering techniques, ACT has been used in clinics to treat malignant hematological diseases and many new ACT-based regimens are in different stages of clinical trials. Here, representative ACT approaches are introduced and the opportunities and challenges for clinical translation of ACT are discussed.

Investigating T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), Galectin 9 (Gal-9), CD160 expression and tumor-infiltrating lymphocytes (TILs) and correlation with clinicopathological characteristics of salivary adenoid cystic carcinoma (SACC).
Sixty cases of SACC were detected by immunohistochemical staining to evaluate TIM-3, Gal-9, and CD160 expression and analyze the correlation between TIM-3, Gal-9, CD160 expression and clinicopathologic features by rank-sum test. The association of TILs with TIM-3, Gal-9, and CD160 expression in SACC stromal was done by Chi-square test.
TIM-3 and CD160 overexpression were correlated with recurrence of SACC (p = 0.029, p = 0.007, respectively). High Gal-9 expression was correlated with pathological classification (p = 0.018). The average percentage of TILs was 18.2% in SACC and most of TILs were more likely to occur in minor salivary glands (p = 0.038). Pairwise positive correlations were observed between the expression of TIM-3, Gal-9, and CD160 in tumor cells as well as in TILs, respectively.
Low density of TILs was characteristic of the SACC microenvironment, with upregulation of TIM-3, Gal-9, and CD160 all occurring. However, TIM-3, Gal-9, and CD160 expression in the stromal dependent on the number of TILs represent potential therapeutic targets in SACC.

Previous studies reported the association between Epstein-Barr virus (EBV) and cervical squamous cell carcinoma (CSCC), but its infection pattern and clinical significance unclear. This study aimed to comprehensively investigate the infection pattern, clinicopathology, outcomes, and immunology of this entity in central China. We evaluated a total of 104 untreated CSCC tumor tissue specimens using in situ hybridization for EBV-encoded small RNAs (EBERs), and by employing flowcytometry fluorescence hybridization for human papillomavirus (HPV) genotyping. The expression of EBV latency proteins and immune biomarkers was evaluated and quantified by immunohistochemistry. EBERs transcripts were detected in 21 (20.2%) cases overall (in malignant epithelial cells of 13 cases and in lymphocytes of 8 cases). EBV belonged to latency type I infection in CSCC. The high-risk (HR)-HPV was detected in all of EBV-positive CSCC, and the difference of detection rate of HR-HPV was significant when compared with EBV-negative CSCC (p = 0.001). The specific clinicopathology with increased frequency of advanced clinical stages, tumor-positive lymph nodes, neural invasion, and increased infiltration depth (all p value < 0.05) were observed in cases with EBV. However, EBV infection was found to have no impact on prognosis of patients with CSCC. Increased densities of forkhead box P3 (FoxP3)+-tumor infiltrating lymphocytes (TILs) (p = 0.005) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)+-TILs (p = 0.017) and higher expression of programmed cell death-1 (PD-1) (p = 0.002) and programmed cell death-1 ligand 1 (PD-L1) (p = 0.040) were associated with EBV latent infection in CSCC, and these immunological changes were more likely to be associated with the infection in lymphocytes rather than tumor cells. Moreover, in patients with HPV-positive CSCC, similar significant differences were still found. In conclusions, EBV-positive CSCC may have specific infection pattern and clinicopathology and can exhibit an immunosuppressive microenvironment dominated by Treg cells aggregation and immune checkpoint activation.

UNASSIGNED: Sarcopenia is associated with poor prognosis in patients with colorectal cancer (CRC), but the mechanisms contributing to this association remain unclear. We hypothesized that skeletal muscle status is associated with tumor-infiltrating lymphocytes (TILs) in patients with CRC. Therefore, this study investigated the clinical effect of sarcopenia and its relationship with the local immune system in CRC patients.
UNASSIGNED: A total of 256 consecutive patients with CRC who underwent curative resection between 2008 and 2014 were enrolled. Sarcopenia was determined according to the skeletal muscle index (SMI), which was assessed using L3 skeletal muscle mass on axial computed tomography images, and its relationship with patient clinicopathological characteristics and survival was evaluated. Additionally, TILs (CD3+, CD8+, CD4+, and FOXP3+ T cells) were assayed by immunohistochemistry. The relationship between TILs and skeletal muscle status was evaluated.
UNASSIGNED: Patients with a lower SMI showed significantly shorter recurrence-free and overall survival compared with those with a higher SMI. Low expression of TILs was associated with significantly shorter recurrence-free survival. SMI was significantly correlated with the number of CD3+ and CD8+ cells in the ordinal logistic regression analysis. Patients with low skeletal muscle status and low CD3+ and CD8+ cells had an unfavorable prognosis compared with patients with high skeletal muscle status and high CD3+ and CD8+ cells.
UNASSIGNED: Our data showed an association between skeletal muscle status and local immune cells, and this association may play a pivotal role in the clinical outcome of patients with CRC.

COVID-19 is leading to a global pandemic and invades human cells via ACE2. ACE2 was found to be abundantly expressed in many organs and cells. However, there is no evidence about the potential risk of various types of cancer patients vulnerable to the infection of COVID-19. To obtain a risk map that indicates the novel coronavirus vulnerability of different types of cancer, we analyzed in this work the RNA sequencing datasets of cancer patients. By interrogating the datasets, we not only identified the cancer types vulnerable to COVID-19 attacks, but also we reported that variations in the mRNA expression level of ACE2 correlate to various prognosis phenomenon in different types of cancer cohorts, and illustrated the underlying mechanism involved or may be related to lymphocytes infiltration. From these discoveries, we constructed an infection risk map, which indicates the vulnerability of different types of cancer to COVID-19 infection, also elucidated the correlationship between ACE2 and the prognosis of cancer. We found that high ACE2 expression levels lead to high risk of COVID-19 infection and poor prognosis of breast invasive carcinoma (BRCA), while better prognosis in ovarian serous cystadenocarcinoma (OV) patient cohorts. Moreover, our study demonstrated that this different pattern may correlate with the immune infiltration level.

Microsatellite instability (MSI)-high (MSI-H) colorectal cancer is known to be associated with increased tumor-infiltrating lymphocytes (TILs), elevated host systemic immune response, and a favorable prognosis. In gastric cancer, however, MSI status has rarely been evaluated in the context of TILs and systemic immune response.
We evaluated data for 345 patients with gastric cancer who underwent gastrectomy with MSI typing. The numbers of TILs were counted after immunohistochemical staining with anti-CD3, CD4, CD8, forkhead box P3 (Foxp3), and granzyme B to quantify the subsets of TILs. To evaluate the systemic immune response, the differential white blood cell count and prognostic nutritional index (PNI) were obtained.
Of the 345 patients, 57 demonstrated MSI-H tumors and 288 demonstrated non-MSI-H tumors. MSI-H tumors carried significantly higher densities of CD8+ T cells, Foxp3+ T cells, and granzyme B+ T cells and a higher ratio of Foxp3/CD4 and granzyme B/CD8. The prognostic impact of TILs differed between patients with MSI-H tumors and those with non-MSI-H tumors. The TIL subsets were not found to be significant prognostic factors for recurrence-free survival (RFS) or overall survival (OS) in the MSI-H tumor group. In the non-MSI-H tumor group, multivariate analysis showed that stage, PNI, and CD4+ T cells were independent prognostic factors for RFS, and stage, PNI, and the Foxp3/CD4 ratio were independent prognostic factors for OS.
The association between systemic/local immune response and prognosis differed according to MSI status. Different tumor characteristics and prognoses according to MSI status could be associated with the immunogenicity caused by microsatellite instability and subsequent host immune response.
This study demonstrates that the density of each subset of tumor-infiltrating lymphocytes (TILs) differed between microsatellite instability (MSI)-high and non-MSI-high tumors. Moreover, the prognostic effect of the preoperative systemic immune response status and TILs differed between the MSI-high (MSI-H) and non-MSI-H tumor groups. The present study may help to identify the mechanisms of cancer progression and develop treatment strategies for MSI-high gastric cancer.

Juvenile-onset recurrent respiratory papillomatosis (JO-RRP) is a human papilloma virus-mediated progressive benign neoplasm that affects children and young adults. Primary management consists of regular surgical debulking to maintain airway patency and vocal function. Like condyloma acuminata, JO-RRP is associated with immune dysregulation, and T cells isolated from papillomas express an anergic phenotype. Therefore, we hypothesized that programmed death protein 1 axis inhibition could stabilize tumor growth.
We treated two patients with refractory JO-RRP using nivolumab, with the primary objective of assessing clinical activity. We explored baseline papilloma features using immunohistochemistry and comprehensive genomic profiling.
Both patients experienced symptomatic improvement, and interval laryngoscopies revealed a reduction in papillomatosis burden. One patient has not required subsequent surgical debridement for almost 2 years. On pathologic examination of pretreatment papillomas from both cases, infiltrating T cells were evident in the papilloma stroma, and papilloma programmed death ligand 1 expression was absent. Papilloma mutational load ranged between three and six mutations per megabase for each case. From on-treatment biopsy tissue, a higher amount of intraepithelial T cells and programmed death ligand 1 expression were detected in the papilloma.
Nivolumab appears to have promising activity in JO-RRP, and further clinical investigation with more patients in clinical trials is warranted.
To the authors\' knowledge, this article is the first report describing clinical activity with a programed cell death-1 (PD-1) inhibitor to treat a rare but detrimental type of respiratory tract epithelial neoplasm that afflicts young adults. Two patients were treated, and tumor features, such as mutational load, were examined with the intent to stimulate future hypotheses for translational research. The safety and activity of PD-1 inhibitors in this population still need to be corroborated in clinical trials and should not yet be adopted into clinical practice.