Given that dendritic cells are necessary for anti-tumor response, researchers investigated which pathways stop these cells from performing their full functions.
New research presented at the 2022 International Cancer Immunotherapy Conference suggests that the addition of an anti-TIM-3 monoclonal antibody could strengthen the anti-tumor effects of paclitaxel and docetaxel.
Dendritic cell functionality is known to drive the cancer immunity cycle, according to presenter Brian Ruffell, PhD, from Moffitt Cancer Center. Conventional type 1 dendritic cells (cDC1s) are required to initiate antigen response by transferring the antigen from the tumor into the lymph nodes and are then required to stimulate the responding T cells. In his own research, Ruffell said he has focused on the role of dendritic cells in regulating the tumor microenvironment.
Given that dendritic cells are necessary for the anti-tumor response, Ruffell said there must be multiple pathways stopping these cells from performing their full functions. In a study of inhibitory molecules expressed in polyoma middle tumor-antigen (PyMT) tumors, the researchers noted that TIM-3 was highly expressed.
TIM-3 is a broadly expressed DC1 molecule, which is also expressed in type 2 dendritic cells (DC2s), although at lower levels. Its high expression was not only found in mouse models but was also seen in breast carcinomas and at slightly lower levels in breast tumor dendritic cells. Minimal expression was found in CD4+ and CD8+ T cells.
After this original finding, the team continued investigating the role of TIM-3 and found that TIM-3 blockade promoted response to paclitaxel. Paclitaxel alone had moderate effects on tumor volume, but with TIM-3 blockade there was strong progression of growth at least for the duration of treatment. The team also noted that efficacy of chemotherapy and TIM-3 blockade is dependent on cDC1s.
Ruffell said that anti-TIM-3 treatments did not promote CD8+ T cell infiltration and there were no effects on CD4 T cells. He assumed that T cells must be recruited into the tumor based on the higher levels measured, but when quantified, they found no evidence of a change in the concentration of cells.
Instead, the team found that anti-TIM-3 promoted cDC1-CD8+ T cell spatial co-localization. When looking at mouse models, the researchers found that cells were largely located proximal to CD1, but with TIM-3 blockade, many more of the cells were within 100 microns of the control tumors. This suggests that anti-TIM-3 efficacy depends upon interleukin-12 production by cDC1s, Ruffell said.
In the second half of his presentation, Ruffell reviewed how TIM-3 suppresses CXCL9 expression by dendritic cells. CXCL9 is one of the chemokines that plays a role in inducing chemotaxis, promoting differentiation and multiplication of leukocytes, and causing tissue extravasation.
Using an in vitro system, researchers isolated dendritic cells, stimulated them with antibodies to mimic the tumor microenvironment, and then examined CXCL9 expression after 6 hours. They found that TIM-3 suppresses a type 1 interferon response.
Further research found that increased CXCL9 expression requires extracellular DNA. Based on this, Ruffell said the next obvious path was activation of the cGAS and STING pathway, which is one of the more common and well understood pathways in cancer.
The team did find that the STING pathway was activated, confirming that the response to anti-TIM-3 requires cGAS and STING. Specifically, the response requires cDC1 expression of the STING pathway.
Finally, Ruffell said his team has found that paclitaxel and docetaxel both induce large quantities of the HMGB1 protein. This could be used to screen for combination therapies and potential combinations with TIM-3 blockade, which the researchers have confirmed can reduce tumor growth.
Ruffell B. Therapeutic Targeting of Intratumoral Dendritic Cells. Presented at: 2022 International Cancer Immunotherapy Conference. September 29, 2022.