Relapse or eradication of cancer is predicted by peptide-major histocompatibility complex affinity.

Cancers often relapse after adoptive therapy, even though specific T cells kill cells from the same cancer efficiently in vitro. We found that tumor eradication by T cells required high affinities of the targeted peptides for major histocompatibility complex (MHC) class I. Affinities of at least 10 nM were required for relapse-free regression.

A systematic analysis of experimental immunotherapies on tumors differing in size and duration of growth.

We conducted a systematic analysis to determine the reason for the apparent disparity of success of immunotherapy between clinical and experimental cancers. To do this, we performed a search of PubMed using the keywords "immunotherapy" AND "cancer" for the years of 1980 and 2010. The midspread of experimental tumors used in all the relevant literature published in 2010 were between 0.

Spleen cells from young but not old immunized mice eradicate large established cancers.

Purpose: Solid tumors that have grown two weeks or longer in mice and have diameters larger than 1 cm are histologically indistinguishable from autochthonous human cancers. When experimental tumors reach this clinically relevant size, they are usually refractory to most immunotherapies but may be destroyed by adoptive T-cell transfer. However, TCR-transgenic T cells and/or tumor cells overexpressing antigens are frequently used in these experiments.

Densely granulated murine NK cells eradicate large solid tumors.

Natural killer (NK) cells inhibit early stages of tumor formation, recurrence, and metastasis. Here, we show that NK cells can also eradicate large solid tumors. Eradication depended on the massive infiltration of proliferating NK cells due to interleukin 15 (IL-15) released and presented by the cancer cells in the tumor microenvironment.

The road to the discovery of dendritic cells, a tribute to Ralph Steinman.

While it was known by the 1960s that lymphocytes mediated adaptive immunity, it was unknown how antigens stimulated lymphocytes. Between 1967 and 1973, we reported that a rare cell type in murine spleen cells took up antigen and were obligatory for T cell dependent and independent antibody responses. We referred to them as A cells or the third cell type.

Targeting stroma to treat cancers.

All cancers depend on stroma for support of growth. Leukemias, solid tumors, cancer cells causing effusions, metastases as well as micro-disseminated cancer cells release factors that stimulate stromal cells, which in turn produce ligands that stimulate cancer cells. Therefore, elimination of stromal support by destroying the stromal cells or by inhibiting feedback stimulation of cancer growth is in the focus of many evolving therapies.

Progression of cancer from indolent to aggressive despite antigen retention and increased expression of interferon-gamma inducible genes.

Many cancers escape host immunity without losing tumor-specific rejection antigens or MHC class I expression. This study tracks the evolution of one such cancer that developed in a mouse following exposure to ultraviolet light. The primary autochthonous tumor was not highly malignant and was rejected when transplanted into naïve immunocompetent mice.

Prevention of renal allograft rejection without immune suppression: a model to revisit.

Spectacular success in preventing renal allograft rejection in rats was obtained over 40 yr ago using only the reactants of the response: donor-type antigen and homologous antiserum directed against donor-type antigen. Tolerance was antigen specific and sustained by persistent antigen of the graft. The model has never been tested rigorously in a large species, though the rationale for why the procedures should work applies across species including humans.

IFN-gamma- and TNF-dependent bystander eradication of antigen-loss variants in established mouse cancers.

Tumors elicit antitumor immune responses, but over time they evolve and can escape immune control through various mechanisms, including the loss of the antigen to which the response is directed. The escape of antigen-loss variants (ALVs) is a major obstacle to T cell-based immunotherapy for cancer. However, cancers can be cured if both the number of CTLs and the expression of antigen are high enough to allow targeting of not only tumor cells, but also the tumor stroma.

Equilibrium between host and cancer caused by effector T cells killing tumor stroma.

The growth of solid tumors depends on tumor stroma. A single adoptive transfer of CD8(+) CTLs that recognize tumor antigen-loaded stromal cells, but not the cancer cells because of MHC restriction, caused long-term inhibition of tumor growth. T cells persisted and continuously destroyed CD11b(+) myeloid-derived, F4/80(+) or Gr1(+) stromal cells during homeostasis between host and cancer.

Induced sensitization of tumor stroma leads to eradication of established cancer by T cells.

Targeting cancer cells, as well as the nonmalignant stromal cells cross-presenting the tumor antigen (Ag), can lead to the complete destruction of well-established solid tumors by adoptively transferred Ag-specific cytotoxic T lymphocytes (CTLs). If, however, cancer cells express only low levels of the Ag, then stromal cells are not destroyed, and the tumor escapes as Ag loss variants. We show that treating well-established tumors expressing low levels of Ag with local irradiation or a chemotherapeutic drug causes sufficient release of Ag to sensitize stromal cells for destruction by CTLs.

Cancer immunotherapy and preclinical studies: why we are not wasting our time with animal experiments.

Experimental research on the immune response to transplanted tumors has led to pioneering discoveries that laid many of the foundations for the current field of immunology. Experimental research in oncology has proven that murine and human tumors have antigens that are truly cancer specific. This article discusses research investigating how can antigens on cancer cells be used to help eradicate cancer.

The role of stroma in immune recognition and destruction of well-established solid tumors.

Well-established solid tumors (at least 14 days old and >1cm in average diameter) are extremely difficult to eradicate immunologically in mice. Most cancer patients that seek medical attention bear primary or metastatic tumors that have grown for longer and that are larger than the tumors we call established. Therefore, focusing research on the problems of rejecting well-established mouse tumors might help in the development of novel concepts and protocols for destroying tumors in patients.

Inflammation as a tumor promoter in cancer induction.

Opposing effects of inflammation on cancer have been described. Acute inflammation usually counteracts cancer development, while chronic inflammation promotes cancer development. Just as inactivation of the p53 pathway may be universal in the neoplasia, the activation of the NFkappaB pathway may, conversely, be frequent in carcinogenesis, and a requirement for inflammation and promotion.

Bystander elimination of antigen loss variants in established tumors.

Cancers express antigens that are targets for specific cytotoxic T lymphocytes (CTLs). However, cancer cells are genetically unstable. Consequently, sub-populations of cancer cells that no longer express the target antigen may escape destruction by CTLs and grow progressively.

C-kit+ FcR+ myelocytes are increased in cancer and prevent the proliferation of fully cytolytic T cells in the presence of immune serum.

Immunogenic cancers induce both IgG antibodies and CD8(+) cytotoxic T lymphocytes (CTL). Rejection of almost all immunogenic tumors depends ultimately on CTL. When tumors grow progressively, IgG continues to be produced but CTL may no longer be demonstrable.

Increasing tumor antigen expression overcomes "ignorance" to solid tumors via crosspresentation by bone marrow-derived stromal cells.

To explain why solid cancers grow or are rejected, we examined how the tumor stroma affected the level of antigen expression necessary to induce an immune response. We applied a tamoxifen-regulated Cre-loxP system to induce a model SIYRYYGL antigen recognized by the 2C T cell receptor. Solid tumors expressing the antigen at lower levels grew, whereas solid tumors expressing antigen induced to 26-fold higher levels were rejected.