Tregs by themselves aren’t necessarily predictive of response. I think we need to specifically focus on their CTLA-4 expression and densities in locations where T cell activation/priming occurs, e.g. intratumoral, draining lymph nodes, and spleen. It is the CTLA-4 on Tregs, not exhausted CD8 T cells, that are preventing most of the priming of effector cells. They are hijacking CD80 and CD86 on conventional dendritic cells, thus preventing co-stimulation with CD28 on T cells.
I think this can be overcome in several ways. First, intratumoral electroporated IL-12 with FLT3 ligand or the combination with highly focused radiotherapy of the primary tumor. The goal would be to expose all tumor antigens to a large pool of antigen presenting cells. This would help to overwhelm CTLA-4 expression on Tregs and allow more priming of effector T cells.
Second, you could also administer antiCTLA-4 therapy intratumorally or in lymphatic tissue where the Tregs do their hijacking. I think it would still be essential to get the tumor antigens released, therefore electroporation or targeted radiotherapy would be necessary. Adding IL-12 and FLT3L would probably result in dramatic immune responses and successful tumor regression.
There is zero doubt in my mind that Tregs need to be addressed in anti-pd-1 refractory patients. You simply won’t get priming if CD80 and CD86 are missing from dendritic cells. Antigen presentation also requires the machinery (dendritic cells) and availability of tumor specific antigens. And you won’t get tumor antigens released unless the cancer cells die. That is why electroporation or highly targeted radiotherapy is going to be key.
Tregs help to protect our internal organs from autoimmunity. They help to maintain homeostasis. But imagine cancer cells developing in that immunosuppressive environment... you don’t have much of a chance to develop adaptive immunity. I first thought about the role of Tregs when my wife developed ovarian clear cell carcinoma at 39 years old. We were pregnant at the time. She had endometriosis apparently for quite a long time. Chronic inflammation can damage cells. Your body’s inflammatory processes retreat during pregnancy and you begin to observe higher frequencies of Tregs. In the context of this new immunosuppressive environment, my wife’s cancer cells spread and her lesions grew adjacent to the endometriosis. Tregs were in control protecting our baby from autoimmunity in the uterus while simultaneously facilitating cancer growth. My wife ultimately had her lesions and one ovary removed and has been in remission following chemotherapy.
I don’t think there is a point of no return with the right combination of immunotherapy. It comes down to maximizing tumor antigen presentation and preventing CTLA-4 hijacking of the antigen presentation machinery. Once that is achieved, then you will witness effector T cell activation and sustained local and abscopal responses. The problem with so many companies developing combo drugs is that they aren’t really focusing on the priming phase in the immunity cycle.
