Sequential Anti-PD1 Therapy Following Dendritic Cell Vaccination Improves Survival in a HER2 Mammary Carcinoma Model and Identifies a Critical Role for CD4 T Cells in Mediating the Response
| Autor: | Krithika N. Kodumudi, Ganesan Ramamoorthi, Colin Snyder, Amrita Basu, Yongsheng Jia, Sabrina Awshah, Amber P. Beyer, Doris Wiener, Lian Lam, Hongtao Zhang, Mark I. Greene, Ricardo L. B. Costa, Brian J. Czerniecki |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
CD4-Positive T-Lymphocytes Receptor ErbB-2 medicine.medical_treatment Programmed Cell Death 1 Receptor B7-H1 Antigen Targeted therapy Th1 0302 clinical medicine PD-1 Immunology and Allergy Cytotoxic T cell skin and connective tissue diseases Original Research Mice Inbred BALB C biology Combined Modality Therapy 3. Good health Tumor Burden medicine.anatomical_structure Treatment Outcome Female lcsh:Immunologic diseases. Allergy PD-L1 T cell Immunology CD4 T cells Breast Neoplasms Mice Transgenic Antibodies Monoclonal Humanized Cancer Vaccines 03 medical and health sciences Immune system breast cancer HER2 Cell Line Tumor MHC class I medicine Animals Humans dendritic cells neoplasms Tumor microenvironment business.industry Mammary Neoplasms Experimental Dendritic cell immune checkpoints Survival Analysis Rats 030104 developmental biology biology.protein Cancer research lcsh:RC581-607 business CD8 030215 immunology |
| Zdroj: | Frontiers in Immunology Frontiers in Immunology, Vol 10 (2019) |
| ISSN: | 1664-3224 |
| Popis: | Patients with metastatic HER2 breast cancer (MBC) often become resistant to HER 2 targeted therapy and have recurrence of disease. The Panacea trial suggested that HER2 MBC patients were more likely to respond to checkpoint therapy if TIL were present or if tumor expressed PD-L1. We assessed whether type I polarized dendritic cells (DC1) could improve checkpoint therapy in a preclinical model of HER2+ breast cancer. TUBO bearing mice were vaccinated with either MHC class I or class II HER2 peptide pulsed DC1 (class I or class II HER2-DC1) concurrently or sequentially with administration of anti-PD-1 or anti-PDL1. Infiltration of tumors by immune cells, induction of anti-HER2 immunity and response to therapy was evaluated. Class I or class II HER2-DC1 vaccinated mice generated anti-HER2 CD8 or CD4+ T cell immune responses and demonstrated delayed tumor growth. Combining both MHC class I and II HER2-pulsed DC1 did not further result in inhibition of tumor growth or enhanced survival compared to individual administration. Interestingly class II HER2-DC1 led to both increased CD4 and CD8 T cells in the tumor microenvironment while class I peptides typically resulted in only increased CD8 T cells. Anti-PD-1 but not anti-PD-L1 administered sequentially with class I or class II HER2-DC1 vaccine could improve the efficacy of HER2-DC1 vaccine as measured by tumor growth, survival, infiltration of tumors by T cells and increase in systemic anti-HER2 immune responses. Depletion of CD4+ T cells abrogated the anti-tumor efficacy of combination therapy with class II HER2-DC1 and anti-PD-1, suggesting that tumor regression was CD4 dependent. Since class II HER2-DC1 was as effective as class I, we combined class II HER2-DC1 vaccine with anti-rat neu antibodies and anti-PD-1 therapy. Combination therapy demonstrated further delay in tumor growth, and enhanced survival compared to control mice. In summary, Class II HER2-DC1 drives both a CD4 and CD8 T cell tumor infiltration that leads to increased survival, and in combination with anti-HER2 therapy and checkpoint blockade can improve survival in preclinical models of HER2 positive breast cancer and warrants exploration in patients with HER2 MBC. |
| Databáze: | OpenAIRE |
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