Cancer immunology research最新文献

Pseudomonas aeruginosa infection is still a serious problem among immunocompromised patients who have advanced urinary tract malignancies, yet the impact of P. aeruginosa on disease progression remains poorly defined. Here, we show that urinary tract infections (UTI) caused by P. aeruginosa exacerbated bladder cancer progression in murine models, primarily by inducing an immunosuppressive tumor microenvironment. Mechanistically, P. aeruginosa activated Toll-like Receptor 5 (TLR5) on bladder cancer cells, triggering phosphorylation of ERK1/2 and subsequent secretion of the chemokine CCL20. This signaling axis promoted the recruitment of myeloid-derived suppressor cells (MDSCs), thereby reinforcing immunosuppression within the tumor microenvironment and exacerbating bladder cancer growth. In clinical samples, 16S rRNA sequencing and transcriptome analysis of bladder cancer tissues confirmed the presence of P. aeruginosa, with its abundance significantly correlating with advanced disease stages and elevated CCL20 expression. Collectively, these data identify a role for P. aeruginosa in promoting bladder cancer progression through TLR5-ERK1/2-CCL20-mediated MDSC recruitment, shedding light on the intricate interplay between microbial infection and cancer pathogenesis. These insights highlight potential therapeutic targets to disrupt infection-driven cancer progression.

Thymomas are rare thymic epithelial tumors harboring a high but variable proportion of lymphocytes without obvious function. Autoimmunity is present in one third of patients at diagnosis. In this study, we performed a phenotypic, single-cell RNA sequencing and spatial analysis of both the T cells and tumoral cells. T cells at all stages of T-cell development-from immature to mature-were present in the tumor, suggesting active thymopoiesis in thymoma. However, data generated through multiple approaches suggested a maturation blockade at the double-negative to double-positive stage of T-cell development. In the mature T-cell compartment, the frequency of regulatory T cells was strongly decreased. The single-cell RNA sequencing analysis showed that the transcriptome of tumoral thymic epithelial cells (TEC) was most similar to that of nontumoral medullary TEC, but the expression of key molecules involved in positive and negative selection was defective. Multiplexed IHC consecutive staining revealed a loss of the cortex-medulla zoning in thymoma, which may be related to a decrease in the expression of T cell-targeted chemokines by tumoral TEC. Altogether, these results suggest that the thymopoiesis present in thymoma is abnormal and may be the cause of the prevalent autoimmunity observed in this disease.

The ability of interleukin-12 (IL-12) to stimulate production of interferon gamma (IFN-γ) suggested it might improve the efficacy of low dose interferon alpha (IFN-α). In this phase II trial, patients with metastatic malignant melanoma were administered recombinant human (rh) IL-12 followed by IFN-α2b. Primary endpoints were clinical response and progression-free survival. Secondary objectives were to evaluate the effect of endogenous IFN-γ on JAK-STAT signaling and IFN-regulated genes in peripheral blood mononuclear cells (PBMCs). Patients with advanced melanoma received rhIL-12 on day 1 and IFN-α2b on days 2-6 of a 14-day cycle. rhIL-12 was given intravenously at 300 ng/kg. IFN α2b was dosed at 3×106 units subcutaneously. Plasma IFN-γ was assayed by ELISA; JAK-STAT signaling was measured in PBMCs by flow cytometry. The proportion of responders was assessed via Simon's two-stage design. Thirty-eight patients were enrolled. The regimen was well-tolerated. Two patients achieved a partial response lasting 6 months or longer (5.3%). IL-12 administration led to an increase in mean plasma IFN-γ from 33.57 pg/mL at baseline to a maximum of 564.86 pg/mL and increased expression of STAT1 and STAT2 in PBMCs. Generation of phosphorylated STAT1 and interferon-simulated gene product 15 in response to IFN-α was enhanced following IL-12. rhIL-12 given prior to IFN-α2b stimulated production of IFN γ, which led to increased levels of JAK-STAT signaling intermediates in patient PBMCs. Combination therapy was reasonably well-tolerated but conferred marginal benefit in patients with metastatic melanoma. These results can inform future studies that employ recombinant IL-12 or novel IL-12 constructs.

Low or absent expression of MHC on tumor cells is a presumed mechanism of resistance to immunotherapy, but evidence for this has largely been indirect. Likewise, whether immunotherapy can be effective without tumor MHC expression is also poorly understood. Using genetically engineered mouse tumor cells expressing the model neoantigen ovalbumin, we found that MHC class I-deficient tumor cells, but not MHC class I-sufficient tumor cells, grew progressively when injected subcutaneously into syngeneic C57BL/6 mice. However, combination immunotherapy using agonistic anti-CD40 and dual immune checkpoint blockade (anti-PD-1 and anti-CTLA-4) was equally effective against tumors that did not express the MHC class I H-2Kb allele, MHC class II, or IFNγ receptor across multiple pancreatic tumor lines (regardless of ovalbumin). Moreover, CD4+ T cells, but not CD8+ T cells or perforin, were necessary to mediate immunotherapeutic responses. We excluded a role for CD4+ T cell-instructed macrophage-mediated tumor cell death but observed reprogramming of MHC class II-expressing stromal cells within the tumor after anti-CD40/ICB treatment. These data indicate that cancer immune surveillance by T cells does not absolutely require tumor-expressed MHC class I nor CD8+ T cells but instead can facilitate a clinically relevant remodeling of endothelial cells, further underscoring tumor-extrinsic roles for CD4+ T cells as mediators of tumor rejection and durable immune memory.

Aberrant expression of the oncogene SALL4 is associated with stemness, a more aggressive cancer phenotype, and reduced patient survival in various tumor types, making SALL4 a potential target for cancer immunotherapy. We conducted a transcriptional analysis of SALL4 expression in colorectal cancer tissues and demonstrated that SALL4 was overexpressed in primary tumors and paired liver metastases. Then, we identified the SALL4-derived S9V peptide as a naturally processed peptide that induced specific CD8+ T-cell responses from the peripheral blood of patients with gastrointestinal cancer, whereas no responses were observed in the peripheral blood of healthy donors. Thereafter, we isolated an SALL4-specific T-cell receptor (TCR) that recognized this peptide in the most common HLA molecule in the Caucasian population, HLA-A2, and used this to develop TCR-engineered T cells. In vitro analysis showed that SALL4 TCR-redirected primary CD8+ T cells exhibited cytotoxic effects against SALL4-expressing tumor cells and produced effector cytokines. In vivo, SALL4-TCR T cells significantly reduced tumor growth and improved the survival of tumor-bearing mice. Moreover, SALL4-TCR T cells displayed no toxicity against hematopoietic stem cells. Thus, we conclude that T cells engineered to express a SALL4-specific TCR have the potential to be effective as immunotherapy for solid cancers and pave the way for further clinical development.

Neoantigen-specific T cells recognize tumor cells and are critical for cancer immunotherapies to be effective. However, the transcriptional program controlling the cell fate decisions by neoantigen-specific T cells is incompletely understood. In this study, using joint single-cell transcriptome and T-cell receptor profiling, we mapped the clonal expansion and differentiation of neoantigen-specific CD8+ T cells in the tumor and draining lymph node (LN) in mouse prostate cancer. Neoantigen-specific CD8+ tumor-infiltrating lymphocytes upregulated gene signatures of T-cell activation and exhaustion compared with those recognizing other tumor antigens. In the tumor-draining LN, we identified TCF1+TOX- stem cell memory T cells (TSCM), TCF1+TOX+ progenitor exhausted T cells (TPEX), and TCF1-TOX+ effector-like exhausted CD8+ T cells (TEX) subsets among neoantigen-specific CD8+ T cells. Divergent neoantigen-specific CD8+ T-cell clones with balanced distribution across multiple differentiation fates underwent significantly greater expansion compared with clones biased toward TEX, TPEX, or TSCM. The TPEX subset had the greatest clonal diversity and likely represented the root of neoantigen-specific CD8+ T-cell differentiation, whereas highly clonally expanded effector-like TEX cells were positioned at the branch point in which neoantigen-specific clones exited the LN and differentiated into TEX tumor-infiltrating lymphocytes. TSCM differentiation of neoantigen-specific CD8+ T-cell clones in the LN negatively correlated with exhaustion and clonal expansion of the same clones in the tumor. In addition, the gene signature of neoantigen-specific clones biased toward tumor infiltration relative to lymph node residence predicted a poorer response to immune checkpoint inhibitors by patients with cancer. In conclusion, we have identified a transcriptional program that controls the cell fate choices by neoantigen-specific CD8+ T cells and correlates with clinical outcomes in patients with cancer.

Targeted therapies for NRAS-mutant melanoma remain an unmet clinical need. In this study, we demonstrate that RMC-7977, a preclinical RAS(ON) multiselective inhibitor representative of the investigational agent daraxonrasib (RMC-6236), was able to elicit potent antitumor immune responses across multiple NRAS-mutant melanoma models. Treatment with RMC-7977 led to rapid tumor regressions driven by inhibition of MAPK signaling, upregulation of MHC and PD-L1 proteins, and enhanced infiltration of CD4+ and CD8+ T cells. Complete responses were dependent on adaptive immunity, as both CD4+ and CD8+ T cells were essential for extended survival. Resistance to treatment was marked by reduced T-cell infiltration, loss of MHC class I expression, and expansion of myeloid-derived suppressor cells. Combining RMC-7977 with anti-PD-1 boosted cytotoxic T-cell infiltration, reprogrammed myeloid cells toward an antigen-presenting phenotype, and improved survival in models resistant to PD-1 blockade. Consistent with these preclinical data, objective clinical responses were observed in two patients with NRAS-mutant melanoma treated with daraxonrasib in an ongoing phase I/Ib clinical trial. Together, these data support the continued clinical evaluation of RAS(ON) multiselective inhibitors for the treatment of NRAS-mutant melanoma.

The immune microenvironment is a crucial component of colorectal carcinoma that has been well characterized, but much less is known about the immune microenvironment of colorectal carcinoma precursors. We hypothesized that T-cell infiltrates might differ across the colorectal neoplastic spectrum. We leveraged the prospective cohort incident-tumor biobank method, which provided formalin-fixed, paraffin-embedded tumor tissue specimens (N = 1,825) from 790 colorectal carcinoma precursors (including hyperplastic polyps, sessile serrated adenomas, traditional serrated adenomas, tubular adenomas, tubulovillous adenomas, and villous adenomas) and 1,035 colorectal carcinomas. We performed an in situ multispectral immunofluorescence assay for CD3, CD4, CD8, FOXP3 (negative, low, or high expression), PTPRC (CD45RO and CD45RA), MKI67 (Ki-67), and KRT (keratin) combined with supervised machine learning. CD3+CD4+ cells were more abundant than CD3+CD8+ cells in most precursors. In conventional adenomas, greater villous component correlated with fewer intraepithelial CD3+CD8+ cells. Serrated lesions, including hyperplastic polyps and sessile serrated lesions, exhibited higher densities of intraepithelial CD3+CD8+ cells compared with other precursors and carcinomas. Age strata of patients with precursors (including early-onset precursors) were not associated with differential T-cell infiltration patterns. Compared with invasive colorectal carcinoma, precursors generally showed higher densities of CD3+CD4+ cells and CD3+CD8+ cells with phenotypes of naive (CD45RA+CD45RO-), memory (CD45RA-CD45RO+), and regulatory (FOXP3+Low and FOXP3+High) in intraepithelial and lamina propria/stromal regions. In conclusion, T-cell infiltration patterns vary across different histopathologic types of the colorectal neoplastic spectrum from precursors to invasive carcinomas. Our findings shed light on how the tumor-immune microenvironment evolves during precursor development and progression to colorectal carcinoma.

Human leukocyte antigen class I (HLA-I) is central to tumor immune recognition, but its regulatory mechanisms in cervical cancer remain poorly understood. This study aimed to elucidate the impact of HLA-I regulatory mechanisms on CD8+ T-cell infiltration and identify distinct histotype-specific immune escape strategies across cervical cancer subtypes. Using 98 cervical cancer cases, including squamous cell carcinoma (SCC; n = 53), adenocarcinoma (n = 32), gastric-type adenocarcinoma (GAS; n = 5), small cell carcinoma (Small, n = 4), and mixed histologic types (n = 4), we examined the relationship between CD8+ T-cell infiltration patterns (categorized as infiltrated, excluded, or absent) and HLA-I expression, HLA-A DNA methylation, and HLA-I loss of heterozygosity (LOH). CD8+ T-cell infiltration patterns varied significantly by histologic subtype (P < 0.0001). SCC showed the highest frequency of the infiltrated pattern (73.6%), whereas GAS and Small predominantly displayed an absent pattern. Reduced CD8+ T-cell infiltration correlated with poor survival (P < 0.0001). HLA-I expression mirrored these trends being highest in SCC and lowest in Small and GAS. HLA-A DNA methylation emerged as a key driver of HLA-I downregulation, leading to reduced CD8+ infiltration (P < 0.05). In SCC, both HLA-A methylation and HLA-I LOH contributed to immune evasion; cases lacking these alterations exhibited the highest CD8+ T-cell infiltration levels (P < 0.01). This study identifies distinct HLA-I regulatory mechanisms in cervical cancer, highlighting HLA-A methylation-and particularly HLA-I LOH in SCC-as key drivers of immune evasion. These findings provide a foundation for developing predictive biomarkers and suggest that targeting these specific HLA-I regulatory mechanisms could enhance immunotherapy efficacy.