Therapeutic antibodies mediate their anti-cancer effect through two different Fcγ receptors

Humanized therapeutic monoclonal antibodies play substantial role in cancer immunotherapy. For example, one of the most recognized member of this class is Rituximab (Rituxan), a humanized α-human CD20 monoclonal antibody used for treatment of B cell-derived malignancies.

It is thought that in humans their anti-cancer effects are mainly driven via human Fcγ receptor IIIA (FcγRIIIA)-mediated ADCC (antibody-dependent cellular cytotoxicity).

New study in journal Cell from Jeffrey Ravetch lab provided new evidence that α-human CD20 monoclonal antibody have two distinct anti-cancer effects: one, short term, via FcγRIIIA-mediated ADCC, and second, long-term, via FcγRIIA-mediated anti-cancer T cell priming.

Of note, the article has only one first author and one senior author.

Initially, the authors confirmed that presence of Fcγ receptors are necessary for anti-cancer effect of α-human CD20 monoclonal antibody.

Next, the authors showed that wild-type mice treated with α-human CD20 monoclonal antibody and challenged with tumor cells expressing hCD20 antigen became "immune" to secondary challenge of hCD20 antigen expressing cancer cells, implying long-term memory development.

The authors showed that this anti-cancer memory was mediated by T cells generated after primary cancer challenge.

Using mice model with selective expression of human Fcγ receptors, the authors showed that primary anti-cancer effect of anti-human CD20 antibodies was restricted to antibody preferentially binding human Fcγ receptor IIIA, thus activating [macrophage]-mediated ADCC pathway.

The authors confirmed this observation with mice transgenic model expressing only human FcγRIIIA.

Conversely, the authors showed that long-term T cell mediated anti-cancer effect of anti-CD20 treatment was driven by FcγRIIA receptors.

In summary, these results provided new evidence how to improve effectiveness of anti-cancer therapeutic antibodies (it appears that commercial antibodies available on the market today target mainly FcγRIIIA, i.e. ADCC pathway). These results also reinforces the idea that successful cancer protection would require activation of several immune pathways (ADCC and T cell priming).

David Usharauli

Foxp3+ Tregs depletion activates anti-cancer immunity via eosinophils

Eosinophils are usually associated with atopic/allergic conditions. However, as with all cells involved in type II immune response, eosinophil's role in host's defense is not entirely clear.

This new paper in Nature Immunology provided evidence for eosinophil's anti-tumor function. The paper itself is quite "primitive", observation-type of research article. It belongs more to JEM, if you ask me. Still, it was accepted within 1 month of its submission to Nature Immunology. 

It appears that initial focus of this research was Foxp3+ Tregs. The authors showed that Foxp3⁺ Tregs depletion in Foxp3.LuciDTR-4 mice induced B16 melanoma rejection expressing nominal OVA antigen (MO4 tumor cells).

Surprisingly, this rejection of MO4 tumor was accompanied with selective eosinophil infiltration at tumor site.

Indeed, concomitant depletion of eosinphils with Siglec-F antibody significantly reduced anti-cancer effect seen with Foxp3⁺ Tregs depletion.

Additional experiments showed that anti-tumor effectiveness of adoptively transferred OVA-specific CD8 T cells were eosinophil dependent, though only in vitro IFN-γ + TNF-α activated, but not resting eosinophils could provide such help to CD8 T cells. Eosinophils alone were not effective.

The authors went on to show that activated eosinophils attracted CD8 T cells to tumor site and promoted normalization of tumor vasculature.

In summary, these results suggests that depletion of Foxp3⁺ Tregs activates eosinophils which in turn recruit CD8 T cells into tumor site leading to anti-tumor effect.

Now, why are eosinophils specifically involved in tumor protection in this model is not clear. What attracts eosinophils into tumors?

David Usharauli

Reciprocal T subset-specific tumor protection by RNA vaccine encoding mutant MHC class I and II binding epitopes

Efficacy of solid cancer immunotherapy mostly depends on effector activity of T cells. Initially, CD8 T cells were thought to mediate primary anti-tumor activity. However, for the past 15 years, growing evidence pointed to a stand-alone CD4 T cell role in cancer protection.      

This new paper in journal Nature provided another example of CD4 T cell specific tumor protection. Strangely, the authors' data suggest that in silico generated MHC class I and II binding mutant epitopes reciprocally activated CD4 and CD8 T cell tumor responses, respectively.

Using three different mouse tumor models, the authors showed that surprisingly mice immunized either with MHC class I binding cancer-specific mutant 27-mer peptide + polyI:C or with MHC class I binding mutant epitope-encoding RNAs, generated predominantly CD4 T cell immunogenic response.   

One of the cancer epitope (B16-M30) encoding RNA even induced fully CD4 T cell-dependent 80% protection of cancer bearing mice.

Strangely, when the authors designed RNAs encoding several MHC class II binding mutant epitopes in combination with one class I binding epitope (synthetic RNA pentatope), anti-tumor protection was CD8 T cell-dependent.

Even more strangely, when the authors designed RNA pentatopes with only MHC class II binding epitopes (based on in silico algorithm and expression level), anti-tumor protection was also CD8 T cell-dependent.

In summary, the authors showed that tumors carry multiple (sometimes hundreds) of mutations that can specifically bind to MHC class II molecules. However, why were epitopes selected based on prediction to bind class I molecules induced CD4 T cell-dependent anti-tumor response (and vice versa for class II epitopes and CD8 T cells) are not clear.

David Usharauli