Almost every cancer patient harbors tumor-specific T cells

We know now that adaptive immune system (T and B cells) can detect single amino acid changes in mutated proteins. However, such efficiency of immune system was (and still) in odds with cancer development since tumors invariably express mutated proteins. So what's the deal?

Until recently in vitro detection of tumor-specific immune response was technically challenging. First, detection of mutated proteins or RNA was not easy task. Second, culture conditions for expansion and identification of viable tumor-infiltrated lymphocytes (TIL) specific for tumor antigens were not easy either. Today we have different situation. We can both detect and identify both tumor antigens and tumor antigen-specific TILs.

For example, new paper in Science showed that 9 out of 10 patients with GI tract cancers harbor tumor-specific T cells. However, out of 4 patients receiving adoptive transfer of in vitro expanded tumor-specific T cells, only 1 patient showed persistent anti-cancer response.

This study is kind of follow up from earlier study published in 2014. Here, for each cancer patient, the authors [led by Steven Rosenberg/NIH] first identified cancer mutations by rapid RNA sequencing and designed dozen of tandem minigene constructs containing mutated RNA sequences. These TMGs were then transfected into patient's autologous DCs and co-cultured with multiple TIL cultures harvested from metastatic tumors. This technique revealed presence of tumor-specific T cells (example below, TMG7, 14).

These tumor-specific TCRs were cancer antigen specific [showed no reactivity towards wild-type epitopes].

In 1 patient, the authors found TIL culture reactive to cancer driver gene KRAS (KRAS^G12D). The authors could identify HLA allele presenting mutated peptide (the authors even filed a patent for TCR directed to mutant KRAS. But the TCR itself is a product of nature and not patent eligible and TCR transduction into other T cells is by now considered "prior art". So I am not sure if they have a valid patent claim here. Another point is that it is safe to assume the authors already have earlier patents for transduction techniques and other TCRs. If so, then why they would need a new patent for just another TCR?).

however, the most relevant results are not shown in the paper but just discussed. The authors mentioned that 4 patients were treated with adoptively transferred T cells. However, only 1 patient receiving tumor-specific CD4 T cells showed persistent response and ongoing tumor regression, while other 3 patients who received tumor-specific CD8 T cells either do not show any response or showed only transient response. This suggest that unlike CD4 T cells, tumor-specific CD8 T cells may be not very efficient against solid tumors [lack of persistence in transferred hosts].

In summary, this article supports a notion that cancers do not go unnoticed by immune system. It appears that almost every cancer patient harbor tumor specific T cells that can be harvested, expanded and re-introduced back to patients to target tumors [alone or in combination of checkpoint inhibitors]. However, understanding biological difference between effectiveness of tumor-specific CD8 and CD4 T cells surely requires further research.  

David Usharauli

Specialized monocyte subset protects lung vasculature from tumor metastases

Immune system's cellular lineage diversity is expanding and quite rapidly. Now we have several types of T cells, several types of NK cells, whole new family of innate lymphoid cells (ILCs), cytokine-secreting B cells, specialized subset of neutrophils using sticky DNA nets to trap the microbes. 

Here comes a paper in Science showing a new subset of orphan nuclear receptor Nur77-positive monocytes specializing in protection of lung vasculature from tumor metastases.

First, using reporter mice that tracks Nur77⁺monocytes (encoded by Nr4a1, a Nr4a1-GFP green mice), the authors showed that after intravenous injection of red fluorescent Lewis Lung Carcinoma cells (LLC-RFP), Nur77⁺monocytes are rapidly accumulating in the lung vasculature, then slowing down their speed in close proximity to tumor cells.

To confirm that Nur77⁺monocytes play a role in tumor defense, the authors first repeated the same experiment with total Nr4a1-KO mice, which according to the authors, selectively lack Nur77⁺monocytes. Nra1-KO mice appeared to harbor more lung metastasis (but not in liver), even if tumor cells [B16 melanoma] were injected subQ.

Similarly, increased tumor metastases (but not primary tumors) were seen with mouse model of spontaneous mammary tumor, MMTV-PyMT, receiving Nr4a1-KO bone marrow transfer, supporting the role of Nur77⁺ hematopoietic cells in prevention of tumor metastases.

To more specifically address the role of Nur77⁺monocytes in tumor protection, the authors have used two different myeloid-specific Nr4a1 conditional knockout models, CSF1R-Cre⁺ Nr4a1^fl/fl and LysM-Cre⁺ Nr4a1^fl/fl. In both models, there was an increase in tumor metastases to the lung. Interestingly, T cell-specific Nur77 deletion showed no effect on tumor metastases.

Finally, the authors found that receptor CX3CR1 could play an important role in tumor recognition by Nur77⁺monocytes.

In summary, this study suggest that there is a specialized monocytes lineage defined by Nr4a1 expression that specifically patrol and protects the lung vasculature against tumor metastases.

David Usharauli

Tumor converts neutrophils into metastasis-promoting cells via γδ T cell-derived IL-17

Immune system supposed to defend the body from infectious agents and genetically transformed cells (tumors). Usually, at the end of each immune response, that can be quite damaging (immune phase), immune cells will be involved in tissue healing, regeneration or remodeling (adaptation phase). However, sometimes infectious agents or tumors will circumvent these steps and jump directly to adaptation phase and will recruit immune cells to carry out their "agenda" at the expense of the host.

For example, we can speculate that tumor's "agenda" would be to grow and expand (metastasize). However, neither of these possible without local and distant tissue remodeling and its readiness to accommodate (accept) tumor cells. Here is where local immune cells become involved.

New study in journal Nature points to one of those possibilities. The authors showed that in a mouse model of mammary tumor metastasis, neutrophils promotes tumor lung metastasis via IL-17 produced by circulating γδ-T cells.

I would like to point out that the authors have used tumor transplantation model (to have shorter experiments) that is obviously very different from spontaneously arising tumors. Nevertheless, they found that lung or lymph node metastasis of skin transplanted tumor was reduced with neutrophil depletion using α-Ly6G antibody (this antibody supposedly selectively depletes neutrophils since they express it at high level).

Interestingly, tumor metastasis were also reduced in the recipients devoid of adaptive immune system and correlated with reduction of IL-17 and G-CSF (granulocyte colony-stimulating factor) serum levels.

Finally, the authors showed that γδ-T cell depletion or genetic deficiency reduced lung and lymph node metastasis of transplanted tumor.

In summary, these results suggest that tumor cells exploit not yet identified pathways within immune system (γδ-T cells / IL-17 / neutrophils axis) to prepare distant tissues to accommodate tumor colonies coming from original tumor niche. Only by understanding how immune cells interact with normal tissues during or after immune response, could we design ways to block such metastasis.

In general this paper is OK, especially if one considers other papers (two recent papers in JEM) corroborating the idea of IL-17's involvement in tumor initiation and metastasis. However, some data are not clear or not well explained, so not a Nature caliber paper, in my view. For example, in Fig. 3a, treatment with α-IL-17A did not modify IL-17 level in the serum. Also, the authors did not explain why they thought CD8 T cells were protective against metastasis in this model when tumor-bearing RAG KO hosts, which lack CD8 T cells, did not show increased metastasis (Fig. 2d versus. Fig. 3g)?


David Usharauli