Papers of the Week 4/27-5/3

 
Allogeneic IgG combined with dendritic cell stimuli induce antitumour T-cell immunity
This paper started with the goal of trying to better understand why even HLA-matched recipients can still completely reject tumors. They hoped that understanding this mechanism might allow implementation of the pathways involved against a patient's own tumor. As a model, they used B16 melanoma cells, which are syngeneic to C57BL/6 mice, and LMP cells which are syngeneic to 129S1 mice. When the cells were implanted into their respective syngeneic hosts, they grew fine, as expected, but when implanted into the other mouse background (allogeneic) the tumor cells were rejected. They found NK cells were dispensable for rejection, but both CD4 & CD8 T cells, as well as B cells were necessary. Further, they found increased mature dendritic cells at allogeneic tumors, and these dendritic cells had internalized more tumor-derived molecules. However, co-culture of dendritic cells with tumor cells didn't cause tumor antigen uptake. They found allogeneic tumor cells became covered with IgM and IgG antibodies when injected into mice. Additionally, they found that the surface proteins allogeneic antibodies were able to bind more tightly to were typically ones that had polymorphisms that distinguished the proteins between different mouse strains.  

Excitingly, if you took antibodies from allogeneic mice, and injected them into mice that were then injected with syngeneic tumors, they could now reject syngeneic tumors. These effects were all dependent on the Fc receptor, which binds to the Fc on the antibodies. They found that if they incubated tumor cells with allogeneic antibodies, now co-cultured dendritic cells would be activated & be able take up tumor antigens, and present them on MHC. Further, these dendritic cells, if adoptively transferred back into mice whose syngeneic tumors had been removed, could prevent relapse of those tumors. 

Importantly, it seemed that it was not something special about allogeneic IgG, but just the fact the tumor cells were coated in antibodies, that stimulated the dendritic cells. They tested this by showing forced binding of syngeneic IgG onto tumor membrane proteins could similarly mediate dendritic cell uptake. However, they found direct injection of allogeneic IgG into tumors to be insufficient to generate an anti-tumor immune response. They found that the tumor associated dendritic cells were unable to be stimulated by the allogeneic IgG allone. They tested if they could better stimulate an immune response by simultaneously injecting TNF-alpha and anti-CD40 along with the allogeneic IgG, and found this combination could generate complete or near complete responses in a variety of tumor models, both in the injected tumor, and at metastatic sites. 

There are a number of potential applications of this approach. Potentially one could do an adoptive transfer of bone marrow-derived dendritic cells after incubation with autologous tumor coated in allogeneic or other tumor-binding IgG. Alternatively, one could do try their intratumoral injection route of allogeneic or other tumor-binding IgG with anti-CD40 and TNF-alpha. As an aside, CD19 CAR-T patients are already treated with allogeneic IgG (IVIG) due to their B cell aplasia, however allogeneic IgG alone has been tried in cancer, with little benefit observed on its own.

Immunosuppressive plasma cells impede T-cell-dependent immunogenic chemotherapy

Unlike the allogeneic IgG paper, this paper found an immunosuppressive role of an immunoglobulin producing cell, IgA+ B cells. They focused on a mouse model of prostate cancer where they had previously shown B cells could aid in tumor progression and resistance to therapies. Here they look at their role in resistance to oxaliplatin, a platinum based DNA damaging agent, thought to not only kill cells, but also cause an immunogenic cell death. They found B cell deficient mice had an improved response to oxaliplatin, and had increased numbers and activation of CD8+ T cells at the tumor site. They found oxaliplatin induced infiltration of both T cells and B cells, particularly an IgA+ PD-L1+ and IL-10 secreting subset of B cells, with evidence that these cells may also be present in human tumors. Further mechanistic studies showed that TGF-beta signaling was important for oxaliplatin induction of IgA+ B cells, and that blocking either PD-L1 or IL-10 production significantly prevented the tumor-protective effect of the B cells. This potentially suggests a combination of PD-L1/PD-1 blockade with oxaliplatin.

Due to the incredibly exciting data generated in human trials that use different ways to stimulate the immune system, there has been a renewed interest in seeing if any target or therapy also positively affects the immune system, and would make for a rational combination. A previous papers of the week discussed the potential immunomodulatory roles of radiation therapy. The problem is figuring out if these are mild immunomodulatory effects, or if they legitimately can affect treatment outcomes. Most likely further understanding of the mechanisms involved, whether they appear to be at play in human tumors, and the further development of biomarkers of the immune response, will help sort out what's really important.


Other interesting papers this week:

Targeting cancer with kinase inhibitors
Blueprint Medicines ($BPMC) IPO'd this past week, and they also came out with a review on the main focus of their research - kinase inhibitors for cancer therapy. This is a good general introduction to kinase inhibitors and historical successes, with obviously an optimistic viewpoint. It also discusses the variety of mechanisms of resistance that can occur, and the importance of combination therapy to delay onset of resistance. It mentions improving kinase inhibitor specificity as well as a bit about covalent and allosteric kinase inhibitors. Not surprisingly, they also have a section on kinases in immunotherapy. Since kinases are important signaling proteins in many cells, it would not be surprising to see increased attempts at targeting kinases with the goal of immunomodulation.