Antitumor T-cell wars: do CD4s outwit CD8s?

In this issue of Blood, Perez-Diez and colleagues report the findings of a series of side-by-side comparisons on the ability of monoclonal CD4⁺ and CD8⁺ T cells to reject transplanted tumors expressing the cognate antigen. Their model focuses on tumors expressing male-exclusive minor histocompatibility antigens and female T-cell receptor (TCR) transgenic mice, whose only TCRs are specific for male antigens presented either by MHC class I or class II molecules.

In vitro exposure of tumor cells to activated antigen-specific CD8⁺ T cells leads to tumor-cell death, while CD4⁺ cells do not kill malignant cells in vitro. In sharp contrast, the results of in vivo experiments by Perez-Diez and colleagues come as a surprise, revealing that CD4⁺ T cells reject tumors while CD8⁺ T cells fail to do so. This unexpected result was found both upon adoptive transfer experiments and when transplanting tumors expressing male-exclusive minor histocompatibility antigen to the TCR-transgenic female hosts.

Intriguingly, major histocompatibility complex II (MHC II) expression on tumor cells is dispensable for rejection, whereas it is critical in the host mouse. Therefore, one has to assume that male antigens from the tumor are cross-presented by MHC class II molecules on stromal cells, leading to recognition by primed specific CD4⁺ T cells (Figure). This suggests important consequences for the immunotherapy of malignant diseases. First, CD4⁺ T cells have probably been seriously underestimated in their potential for adoptive therapy. Second, CD4-recognizable tumor antigens should be incorporated in antitumor vaccines, not only because they provide help for CTLs, but also because of the CD8-independent antitumor activity of CD4s. For instance, attention must be paid in allogeneic bone marrow transplantation to donor CD4 T cells recognizing minor histocompatibility or tumor antigens.

The mechanisms of the antitumor effect of CD4⁺ T cells against solid tumors have not been fully addressed by Perez-Diez and colleagues. The stromal components of the tumor that can express MHC class II molecules include myeloid cells and activated endothelial cells (Figure). The tumor-rejecting mechanisms of CD4 could involve destruction of tumor blood vessels with cytokines and proapoptosis ligand/receptor pairs. Besides, CD4 Th1 cells are known to activate macrophages and therefore could turn pro–tumor stromal myeloid cells into tumor-destructive activated macrophages. Interestingly, the authors find a key role for host NK cells in tumor rejection. These mechanisms must be further explored to understand this CD4-NK duo, which might involve antiangiogenesis and tumor blood vessel destruction in addition to direct tumor cytolysis (Figure).

The reason for the inferiority of CD8 T cells is less clear. Perez-Diez and colleagues report that in vivo killing activity of adoptively transferred CD8 killers remained normal in tumor-bearing females, but tumors progressed regardless of proper presentation of antigen. Mysteriously, the problem is not lack of early CTL arrival and infiltration into the tumor tissue. The findings of Perez-Diez and colleagues are extremely provocative, yet more models of CD8 TCR transgenic T cells should be analyzed in this context.

With the advent of intravital microscopy technology allowing visualization of the behavior of T cells inside tumors,¹  it will be very interesting to see how CD4⁺ TCR transgenic T cells perform tumor rejections. This article also highlights the tremendous importance of the stromal-cellular components of the tumor as cross-presenters of tumor antigens.^2,3  The good news is that stromal cells are genetically stable and therefore have no propensity to lose the antigen-presenting machinery. Interestingly, stressing tumors with radiotherapy or chemotherapy enhances local cross-presentation.²  The findings of Perez-Diez and colleagues point toward potential new routes of treatment that clinical immunotherapists of cancer have largely overlooked in the past.