Pattern of programmed cell death-ligand 1 expression and CD8-positive T-cell infiltration before and after chemoradiotherapy in rectal cancer

AbstractThe clinical treatment of metastatic spinal tumor remains a huge challenge owing to the intrinsic limitations of the existing methods. Programmed cell death protein 1 (PD1)/programmed cell death ligand 1 (PD-L1) pathway blockade has been explored as a promising immunotherapeutic strategy; however, their inhibition has a low response rate, leading to the minimal cytotoxic T cell infiltration. To ameliorate the immunosuppressive microenvironment of intractable tumor and further boost the efficacy of immunotherapy, we report an all-round mesoporous nanocarrier composed of an upconverting nanoparticle core and a large-pore mesoporous silica shell (UCMS) that is simultaneously loaded with photosensitizer molecules, the IDO-derived peptide vaccine AL-9, and PD-L1 inhibitor. The IDO-derived peptide can be recognized by the dendritic cells and presented to CD8+ cytotoxic T cells, thereby enhancing the immune response and promoting the killing of the IDO-expressed tumor cells. Meanwhile, the near-infrared (NIR) activated photodynamic therapy (PDT) could induce immunogenic cell death (ICD), which promotes the effector T-cell infiltration. By combining the PDT-elicited ICD, peptide vaccine and immune checkpoint blockade, the designed UCMS@Pep-aPDL1 successfully potentiated local and systemic antitumor immunity and reduced the progression of metastatic foci, demonstrating a synergistic strategy for cancer immunotherapy.

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T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas

Cancer ◽

10.1002/cncr.30726 ◽

2017 ◽

Vol 123 (17) ◽

pp. 3291-3304 ◽

Cited By ~ 81

Author(s):

Seth M. Pollack ◽

Qianchuan He ◽

Jennifer H. Yearley ◽

Ryan Emerson ◽

Marissa Vignali ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Soft Tissue ◽

Programmed Cell Death ◽

Soft Tissue Sarcomas ◽

Cell Infiltration ◽

Programmed Death Ligand 1 ◽

T Cell Infiltration ◽

Programmed Death ◽

Cell Death Protein

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The PD-1, PD-L1 expression and CD3+ T cell infiltration in relation to outcome in advanced gastric signet-ring cell carcinoma, representing a potential biomarker for immunotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15609 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15609-e15609 ◽

Cited By ~ 1

Author(s):

Shenying Jin ◽

Bo Xu ◽

Lixia Yu ◽

Yao Fu ◽

Hongyan Wu ◽

...

Keyword(s):

T Cells ◽

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

Signet Ring Cell Carcinoma ◽

Signet Ring Cell ◽

Cell Infiltration ◽

T Cell Infiltration ◽

Signet Ring ◽

Ring Cell

e15609 Background: Recent data supports a potentially significant role for immune checkpoint inhibitors in the treatment of gastric cancer. However, there are few data on the clinical implications of immunotherapy markers in gastric signet-ring cell carcinoma (SRCC). We evaluated the expression of programmed cell death protein-1 (PD-1), programmed cell death ligand 1 (PD-L1), infiltration by CD3+ T cell, microsatellite instability (MSI), and Epstein-Barr Virus (EBV), and the relationship of each factor to survival in SRCC patients. Methods: SRCC samples from 89 patients were stained by immunohistochemistry to evaluate PD-L1, PD-1, CD3+ T cells, and MSI. EBV was detected by DNA in-situ hybridization. Results: All 89 patients had advanced gastric SRCC (89.9% were stage III, 10.1% were stage IV). All patients received 5-FU-based first-line chemotherapy. PD-L1 and PD-1 were expressed in 40.4% and 18.0% of the patients, respectively. There was a significant correlation between PD-L1 and PD-1 expression (r = 0.363, p < 0.001). There was loss of at least 1 of the 4 DNA mismatch repair (DNA-MMR) gene proteins in 32.6% of samples. However, there was no association between the expression of PD-L1, PD-1 or MSI status to overall survival (OS). Only 1 case out of 89 was EBV positive, with concurrent PD-L1 positivity, a high degree of CD3+ T cell infiltration and MSI. Increased CD3+ T cells numbers was associated with increased PD-1 expression (r = 0.256, p = 0.012) and MSI status (r = 0.208, p = 0.05). High CD3+ T cell infiltration was related to better OS (23.7 months, 95% CI: 19.0-38.0 vs 15.8 months, 95% CI: 13.0-22.0, p = 0.033), but was not an independent prognostic factor for survival after multivariate analysis (HR = 0.68, 95% CI: 0.42-1.10, p = 0.116). Conclusions: CD3+ T cell was more infiltrated in PD-1 positive, tumors with MSI and were associated with better OS, indicating an adaptive immune resistance may be occurring. Further research into the cancer characteristics and immunotherapy markers of the gastric SRCC immune microenvironment may highlight targets for immunotherapy.

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Co-delivery of IOX1 and doxorubicin for antibody-independent cancer chemo-immunotherapy

Nature Communications ◽

10.1038/s41467-021-22407-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Jing Liu ◽

Zhihao Zhao ◽

Nasha Qiu ◽

Quan Zhou ◽

Guowei Wang ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Programmed Cell Death ◽

Memory Function ◽

Histone Demethylase ◽

Cell Dysfunction ◽

T Cell Infiltration ◽

Programmed Cell Death 1 ◽

T Cell Dysfunction

AbstractAnti-programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) antibodies are currently used in the clinic to interupt the PD-1/PD-L1 immune checkpoint, which reverses T cell dysfunction/exhaustion and shows success in treating cancer. Here, we report a histone demethylase inhibitor, 5-carboxy-8-hydroxyquinoline (IOX1), which inhibits tumour histone demethylase Jumonji domain-containing 1A (JMJD1A) and thus downregulates its downstream β-catenin and subsequent PD-L1, providing an antibody-independent paradigm interrupting the PD-1/PD-L1 checkpoint. Synergistically, IOX1 inhibits cancer cells’ P-glycoproteins (P-gp) through the JMJD1A/β-catenin/P-gp pathway and greatly enhances doxorubicin (DOX)-induced immune-stimulatory immunogenic cell death. As a result, the IOX1 and DOX combination greatly promotes T cell infiltration and activity and significantly reduces tumour immunosuppressive factors. Their liposomal combination reduces the growth of various murine tumours, including subcutaneous, orthotopic, and lung metastasis tumours, and offers a long-term immunological memory function against tumour rechallenging. This work provides a small molecule-based potent cancer chemo-immunotherapy.

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Abstract A37: CBP501 induces tumor immunogenic cell death and CD8 T cell infiltration into tumor in combination with platinum, thereby increasing the efficacy of immune checkpoint inhibitors against tumors in mice

10.1158/2326-6074.tumimm16-a37 ◽

2017 ◽

Author(s):

Keiichi Sakakibara ◽

Takuji Sato ◽

Donald W. Kufe ◽

Daniel D. VonHoff ◽

Takumi Kawabe

Keyword(s):

Cell Death ◽

T Cell ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Cd8 T Cell ◽

Cell Infiltration ◽

Immunogenic Cell Death ◽

T Cell Infiltration

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High Frequency of CD8 Positive Lymphocyte Infiltration Correlates with Lack of Lymph Node Involvement in Early Rectal Cancer

Disease Markers ◽

10.1155/2014/792183 ◽

2014 ◽

Vol 2014 ◽

pp. 1-7 ◽

Cited By ~ 6

Author(s):

Silvio Däster ◽

Serenella Eppenberger-Castori ◽

Christian Hirt ◽

Inti Zlobec ◽

Tarik Delko ◽

...

Keyword(s):

Rectal Cancer ◽

Lymph Node ◽

T Cell ◽

Lymph Node Involvement ◽

Cell Infiltration ◽

Early Rectal Cancer ◽

Nodal Involvement ◽

T Cell Infiltration ◽

Node Involvement ◽

Rectal Cancers

Aims. A trend towards local excision of early rectal cancers has prompted us to investigate if immunoprofiling might help in predicting lymph node involvement in this subgroup.Methods. A tissue microarray of 126 biopsies of early rectal cancer (T1 and T2) was stained for several immunomarkers of the innate and the adaptive immune response. Patients’ survival and nodal status were analyzed and correlated with infiltration of the different immune cells.Results. Of all tested markers, only CD8 (P=0.005) and TIA-1 (P=0.05) were significantly more frequently detectable in early rectal cancer biopsies of node negative as compared to node positive patients. Although these two immunomarkers did not display prognostic effect “per se,” CD8+ and, marginally, TIA-1 T cell infiltration could predict nodal involvement in univariate logistic regression analysis (OR 0.994; 95% CI 0.992–0.996;P=0.009and OR 0.988; 95% CI 0.984–0.994;P=0.05, resp.). An algorithm significantly predicting the nodal status in early rectal cancer based on CD8 together with vascular invasion and tumor border configuration could be calculated (P<0.00001).Conclusion. Our data indicate that in early rectal cancers absence of CD8+ T-cell infiltration helps in predicting patients’ nodal involvement.

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