We need a renewed focus on our own cancer antibody responses

Antibodies are central to the treatment of cancer—we use them to block certain cell surface receptor signaling, to label cancer cells for destruction by the immune system, and to block signals that are preventing immune responses. We use antibodies in these same roles in infectious disease, and so it would be reasonable to expect that lessons from infectious disease can often be applied to cancer treatment.

We now have technologies to study the antibody responses to infectious diseases in detail, and in the last couple decades we have learned antibodies are an active hub of communication across the immune system. However, we seldom ask how our endogenously produced anti-tumor antibodies (ATAb) might influence cancer progression. Why is this? The standard tale for our progression in understanding cancer immunity is that we expected the immune system could not mount a productive defense for a long time. Checkpoint inhibitors made it clear that an active response is present but halted at its last steps. Given the recent revisions to our mental model of cellular immunity, I have been working through the literature of exactly what we know about our humoral responses. I think the results indicate it is time for a renewed focus on the humoral immune response to cancers.

The immune system naturally develops antibodies against cancer

A humoral immune response is a common feature of cancers. This has most extensively been explored for prototypical surface antigens like mutant EGFR, HER2, and NY-ESO-1. In general, the majority of patients have measurable antibody responses if their tumor is positive for a given marker, and the titers correlated with higher expression of those antigens. HER2 and NY-ESO-1 show that the targets did not have to be mutated but could simply be aberrantly expressed. cDNA expression libraries expanded our ability to identify target antigens in the 1990’s, and tumor-binding antibodies could be identified against surface markers unique to individual patients’ tumors. In fact, many groups have proposed to identify cancers through their uniquely high abundance of auto-antibody staining.

Antibodies have the capacity to eliminate tumors

We know this from years of using therapeutic monoclonal antibodies in which immune effector response is a key feature. A study in mice has also shown that responses to checkpoint inhibition increase ATAb titers, and that this convalescent plasma can be protective on passive immunization.

What are the Fc properties of endogenous antibodies?

Here we reach the limits of our knowledge; if we have these antibody responses, why are they ineffective at eliminating tumors? Since some of the studies on the prevalence of ATAbs in the 1990’s, we have learned that antibodies are quite complicated. An antibody with the same antigen targeting can be pro- or anti-inflammatory, promote different types of immune responses, and is regulated through sequence and post-translational changes. The Fc signal conveyed to the immune system can be modulated in an antigen-specific manner by signals we do not fully understand. While great progress has been made in our ability to characterize the Fc properties of antibodies, I could not find any systematic characterization of those targeting cancer. Even remarkably basic questions, like the isotype distribution of ATAbs, have barely been addressed.

Why care about endogenously produced antibodies when we can provide passive immunity through monoclonal antibodies?

Given our success in developing monoclonal antibody therapies against cancer, why should we care about ATAbs? We can see answers to this question in lessons from infectious diseases. There may not be shared antigens against every patient’s tumor. Even if we were to develop an enormous panel of monoclonal antibody therapies, tumors are relentlessly adaptable. Endogenous immune responses can mature and spread across antigens and so possibly overcome the development of resistance. Finally, ATAbs likely modulate our response to monoclonal therapies. Our lab has been developing tools to ask how antibodies communicate with the immune system when present in combination, and one prevailent feature is widespread antagonism through both antigen and Fc receptor competition. Therefore, ATABs might impede responses to therapeutic antibodies.

Having read through the literature more extensively, I am struck by how much it seems we have ignored this arm of the cancer immune response. There are very basic questions that it seems we now have the tools to answer and can change our approach to treatment:

• When does the ineffectiveness of antibodies arise through antibody properties, cancer properties, or both?
• What are the Fc properties of ATAbs? How do they compare to those in acute and chronic infections?
• How do ATAbs influence the response to therapeutic monoclonals?
• Can we selectively change the properties of ATAbs in vivo? Are there active inhibitory signals ensuring that ATAbs are not tumor destructive?
• Do the Fc properties of ATABs reflect the status of cancer immune responses? Do changes upon treatment influence outcome?

Certainly, there have been frustrating setbacks on the path to cancer immunotherapy. One of those has been cancer vaccines that hoped to unleash an immune response against the disease. However, our understanding now is that an immune response—both cellular and humoral—exists but is generally halted at its last steps. We have learned so much about how to unleash cellular immunity in the last few years, and it is time to free immunity’s other arm.