OBJECTIVE: To evaluate the relationship between kinetic parameters of ultrafast dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and tumor-infiltrating lymphocytes (TILs) in breast cancer.
METHODS: This retrospective study was approved by an institutional review board and included 76 women (median age: 60) with 76 surgically proven breast cancers who underwent DCE MRI including ultrafast sequence. Based on the TILs level, we classified the patients into the low-TILs (< 10%) group and the high-TILs (≥ 10%) group. Maximum slope (MS) and time to enhancement (TTE) derived from ultrafast DCE sequence were correlated in each TILs group. The percentages of six kinetic patterns (fast, medium, and slow from the early phase, washout, plateau, and persistent from the delayed phase) derived from the conventional DCE sequence were also correlated in each TILs group.
RESULTS: Of the 76 breast cancers, 57 were in the low-TILs group and 19 comprised the high-TILs group. The median MS in the high-TILs group (32.4%/sec) was significantly higher than that in the low-TILs group (23.68%/s) (p = 0.037). In a receiver-operating characteristic (ROC) analysis, the area under the curve (AUC) for differentiating between the high- and low-TILs group was 0.661. The TTE in the high-TILs group was significantly shorter than that in the low-TILs group (p = 0.012). In the ROC analysis, the AUC was 0.685. There were no significant differences between the percentages of the six kinetic patterns from the conventional DCE sequence and the TILs level (p = 0.075-0.876).
CONCLUSIONS: Compared to the low-TILs group, the high-TILs group had higher MS and shorter TTE.

UNASSIGNED: Numerous studies underscore the relevance of tumor-infiltrating-lymphocytes (TILs) as important prognostic factors for melanoma. This meta-analysis aims to provide a comprehensive literature overview elucidating their role in predicting patient outcomes, specifically investigating the association between TIL density and prognosis.
UNASSIGNED: From an initial pool of 6094 records, 16 met the eligibility criteria, encompassing a collective cohort of 16021 patients. Data on TIL counts, clinical characteristics, and survival metrics (5-year overall survival [5yOS], 10-year overall survival [10yOS], and 5-year melanoma-specific survival [5yMSS]) were extracted from each study and expressed as proportions. Results were graphically presented using forest plots, reporting the estimates from individual studies, summary estimates, and corresponding 95 % confidence intervals (CI).
UNASSIGNED: Analysis revealed a statistically significant difference in 5yOS concerning subgroup differences However, 10yOS and 5yMSS did not exhibit statistical significance. Nonetheless, a consistent trend emerged indicating a higher survival rate corresponding to increased immune cell density, ranging from absent TILs to brisk levels.
UNASSIGNED: TILs present potential as a readily applicable prognostic factor. Yet, further investigations into their density and phenotypic subpopulation characteristics could enhance our understanding of their predictive value in tailoring optimal patient-specific therapies.

The SWI/SNF complex is a chromatin remodeling complex comprised by several proteins such as SMARCA4 or SMARCB1. Mutations in its components can lead to the development of aggressive rhabdoid tumors such as epithelioid sarcoma, malignant rhabdoid tumor or small cell carcinoma of the ovary hypercalcemic type, among others. These malignancies tend to affect young patients and their prognosis is poor given the lack of effective treatments. Characteristically, these tumors are highly infiltrated by TILs, suggesting that some lymphocytes are recognizing tumor antigens. The use of those TILs as a therapeutic strategy is a promising approach worth exploring. Here, we report the clinical protocol of the TILTS study, a Phase II clinical trial assessing personalized adoptive cell therapy with TILs in patients affected by these tumor types.Clinical Trial Registration: 2023-504632-17-00 (www.clinicaltrialsregister.eu) (ClinicalTrials.gov).
[Box: see text].

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.

The purpose of this multicenter study was to retrospectively investigate the prognostic significance of the tumor microenvironment, in relation to survival in a large cohort of patients with laryngeal squamous cell carcinoma (LSCC), using the method proposed by the International TILs Working Group in breast cancer.
All consecutive patients with biopsy-proven LSCC who underwent total laryngectomy (TL) between January 2014 and January 2023 were retrospectively included in the study. A retrospective review of medical records including surgical, pathological and follow-up reports was performed. The density of TILs was determined according to the recommendations of the International TILs Working Group.
The study group included 186 patients with LSCC. High TILs were statistically correlated with reduced size and extension of primary tumor (pT stage) with a statistically significant value (S: p = 0.01; P: p = 0.0003) and without needs of salvage therapy (S: p = 0.03; P: p = 0.004). Low TILs were indicative of worse prognosis.
Our study confirmed the protective value of TILs and the prognostic role of the tumor microenvironment in LSCC; furthermore, our results showed that the score proposed by the International TILs Working Group for breast cancer can be applied to LSCC.

Human CD8 tumor-infiltrating lymphocytes (TILs) with impaired effector functions and PD-1 expression are categorized as exhausted. However, the exhaustion-like features reported in TILs might stem from their activation rather than the consequence of T cell exhaustion itself. Using CRISPR-Cas9 and lentiviral overexpression in CD8 T cells from non-cancerous donors, we show that the T cell receptor (TCR)-induced transcription factor interferon regulatory factor 4 (IRF4) promotes cell proliferation and PD-1 expression and hampers effector functions and expression of nuclear factor κB (NF-κB)-regulated genes. While CD8 TILs with impaired interferon γ (IFNγ) production exhibit activation markers IRF4 and CD137 and exhaustion markers thymocyte selection associated high mobility group box (TOX) and PD-1, activated T cells in patients with COVID-19 do not demonstrate elevated levels of TOX and PD-1. These results confirm that IRF4+ TILs are exhausted rather than solely activated. Our study indicates, however, that PD-1 expression, low IFNγ production, and active cycling in TILs are all influenced by IRF4 upregulation after T cell activation.

Background: This study aims to retrospectively investigate the prognostic significance of the tumor microenvironment, with a focus on TILs (tumor-infiltrating lymphocytes), in relation to survival in a large cohort of patients with parotid gland cancer, and it uses the method proposed by the International TILs Working Group in breast cancer. Methods: We included a cohort of consecutive patients with biopsy-proven parotid cancer who underwent surgery between January 2010 and September 2023. A retrospective review of medical records, including surgical, pathological and follow-up reports, was performed. The density of TILs was determined according to the recommendations of the International TILs Working Group for breast cancer. Results: A weak negative correlation (p = 0.3) between TILs and time of survival and a weak positive correlation (p = 0.05) between TILs and months of survival (high TILs were correlated with longer survival in months) were identified. High TILs were weakly negatively, but not statistically significantly p (0.7), correlated with the grading of tumor; this means that high TILs were associated with low-grade tumors. Conclusions: Contrary to previous preliminary reports, this retrospective work found no statistically significant prognostic role of TILs in parotid gland malignancies. This case series represents the largest cohort ever reported in the literature and includes all malignant histological types. Future larger molecular studies may be useful in this regard.

Breast cancer poses a global health challenge, yet the influence of ethnicity on the tumor microenvironment (TME) remains understudied. In this investigation, we examined immune cell infiltration in 230 breast cancer samples, emphasizing diverse ethnic populations. Leveraging tissue microarrays (TMAs) and core samples, we applied multiplex immunofluorescence (mIF) to dissect immune cell subtypes across TME regions. Our analysis revealed distinct immune cell distribution patterns, particularly enriched in aggressive molecular subtypes triple-negative and HER2-positive tumors. We observed significant correlations between immune cell abundance and key clinicopathological parameters, including tumor size, lymph node involvement, and patient overall survival. Notably, immune cell location within different TME regions showed varying correlations with clinicopathologic parameters. Additionally, ethnicities exhibited diverse distributions of cells, with certain ethnicities showing higher abundance compared to others. In TMA samples, patients of Chinese and Caribbean origin displayed significantly lower numbers of B cells, TAMs, and FOXP3-positive cells. These findings highlight the intricate interplay between immune cells and breast cancer progression, with implications for personalized treatment strategies. Moving forward, integrating advanced imaging techniques, and exploring immune cell heterogeneity in diverse ethnic cohorts can uncover novel immune signatures and guide tailored immunotherapeutic interventions, ultimately improving breast cancer management.

BACKGROUND: Tumor infiltrating lymphocytes (TILs) are a promising inexpensive prognostic and predictive biomarker in breast cancer. High levels of TILs are associated with improved survival and higher probability to achieve pathological complete response in triple-negative breast cancer (TNBC).
OBJECTIVE: To assess the level of TILs in TNBC samples and analyze the association between the level of TILs and the main pathological parameters, to identify their impact on long-term results.
METHODS: The study included information on 140 patients with I-III stage TNBC and estrogen receptors <10%. Tumor tissue samples at baseline biopsies were evaluated the histological type, HER2 expression, estrogen expression levels, Ki-67 and TILs. The pathological response was evaluated according to the ypTNM, Miller-Payne, and RCB classifications.
RESULTS: The average level of TILs in biopsy specimens before NACT was 29.3±23.1%. Low levels of TILs (<10%) were defined in 21% of cases, intermediate levels (≥10% to ≤40%) in 55% of cases, and high levels (>40%) in 24% of cases. Using the two-tiered system, low TILs (≤40%) were defined in 76% and high TILs (>40%) in 24% of cases. The level of TILs was correlated with histological grade (R=0.187; p=0.027) and estrogen receptor expression level (R=0.211; p=0.012). There were no significant differences depending on the level of TILs and other pathological parameters. Three-year event-free survival (EFS) in patients with high TILs levels was 95% versus 65% in the low TILs group (p=0.037).
CONCLUSIONS: Stromal TILs are an important prognostic biomarker in TNBC. Using a cutoff of 40%, high TILs are significantly associated with longer EFS.
Инфильтрирующие опухоль лимфоциты (TILs) — многообещающий недорогой прогностический и предиктивный биомаркер рака молочной железы. Высокий уровень TILs ассоциирован с лучшими показателями выживаемости и частотой полного патоморфологического ответа при трижды негативном раке молочной железы (ТНРМЖ).
UNASSIGNED: Оценить уровень TILs в образцах ТНРМЖ и проанализировать зависимость между уровнем TILs и основными патоморфологическими показателями, выявить их влияние на отдаленные результаты.
UNASSIGNED: В исследование включены сведения о 140 пациентках с трижды негативным раком молочной железы I—III стадии и с рецепторами эстрогена менее 10%. Исследовались трепанобиоптаты, взятые до начала неоадъювантной химиотерапии (НАХТ), с оценкой гистологического типа опухоли, экспрессии HER2, статуса гормональных рецепторов, индекса пролиферативной активности Ki-67 и уровня TILs. В операционном материале, полученном после НАХТ, проводили оценку степени лечебного патоморфоза по классификациям ypTNM, Miller—Payne, RCB.
UNASSIGNED: Средний уровень TILs в биоптатах до НАХТ составил 29,3±23,1%. Низкий уровень TILs (менее 10%) был выявлен в 21% случаев, средний уровень (от 10% и более до 40% и менее) — в 55% случаев и высокий уровень (более 40%) — в 24% случаев. При разделении когорты пациенток на две группы по уровню TILs в 76% случаев определялся низкий уровень TILs (40% и менее), а в 24% случаев — высокий уровень TILs (более 40%). Уровень TILs положительно коррелировал с гистологической степенью злокачественности (R=0,187; p=0,027) и уровнем экспрессии рецепторов эстрогена (R=0,211; p=0,012). Не было выявлено значимых различий в зависимости от уровня TILs и других патоморфологических показателей. Трехлетняя бессобытийная выживаемость (БСВ) у пациенток с высоким уровнем TILs составила 95% против 65% в группе низкого уровня TILs (p=0,037).
UNASSIGNED: Стромальные TILs являются важным прогностическим биомаркером при ТНРМЖ. При использовании порогового значения в 40% высокие показатели TILs значимо связаны с более длительной БСВ.

Glioblastoma (GBM) is the most common malignancy of the central nervous system in adults. GBM has high levels of therapy failure and its prognosis is usually dismal. The phenotypic heterogeneity of the tumor cells, dynamic complexity of non-tumor cell populations within the GBM tumor microenvironment (TME), and their bi-directional cross-talk contribute to the challenges of current therapeutic approaches. Herein, we discuss the etiology of GBM, and describe several major types of non-tumor cells within its TME, their impact on GBM pathogenesis, and molecular mechanisms of such an impact. We also discuss their value as potential therapeutic targets or prognostic biomarkers, with reference to the most recent works on this subject. We conclude that unless all \"key player\" populations of non-tumor cells within the TME are considered, no breakthrough in developing treatment for GBM can be achieved.